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  • 101.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Endothelium-dependent vasodilation in conduit and resistance vessels in relation to the endothelial nitric oxide synthase gene2008Inngår i: Journal of Human Hypertension, ISSN 0950-9240, E-ISSN 1476-5527, Vol. 22, nr 8, s. 569-578Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Single nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase (NOS3) gene have been related to endothelium-dependent vasodilation in either conduit or resistance arteries with divergent results. In the Prospective Study of the Vasculature in Uppsala Seniors study, 959 participants aged 70 (51% men) were evaluated with brachial artery ultrasound to assess flow-mediated vasodilation (FMD; reflecting conduit arteries) and invasive forearm technique with intrabrachial infusion of acetylcholine (endothelium-dependent vasodilation (EDV); reflecting resistance arteries). The 23 SNPs analysed by minisequencing captured >90% of the common genetic variation in the NOS3 gene, using the HapMap population of European ancestry (CEU) as reference. One SNP (Glu298Asp) was related to FMD (nominal P=0.0018), but not to EDV (nominal P=0.76) after adjustment for sex, systolic blood pressure, diastolic blood pressure, pulse rate, antihypertensive treatment, total cholesterol, high-density cholesterol, lipid-lowering medication, fasting glucose, antidiabetic medication, body mass index, current smoking and prior diagnosis of cardiovascular disease. This relation was significant in both men and women in sex-specific analyses, and remained significant after adjusting for multiple testing (empirical P=0.029 from bootstrap resampling). None of the constructed haplotypes were related to vasodilation. The Glu298Asp SNP in the NOS3 gene was related to endothelium-dependent vasodilation in conduit, but not in resistance arteries. This SNP has previously been related to coronary heart disease, and our findings should stimulate to replication and exploration of the association of NOS3 variation with endothelial function in other settings.

  • 102.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Polymorphisms in the estrogen receptor alpha gene and endothelial function in resistance and conduit arteries in the elderly2008Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 199, nr 1, s. 162-171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Prior evidence suggests an important role for estrogen in the regulation of endothelium-dependent vasodilation, but the mechanisms modulating this are not known. Our aim was to examine the relations of single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) to endothelium-dependent vasodilation.

    METHODS:

    We evaluated 959 70-year-old participants (51% men) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, using invasive forearm technique with intra-brachial infusion of acetylcholine (EDV; reflecting vasodilation in resistance arteries), and brachial artery ultrasound to assess flow-mediated vasodilation (FMD; reflecting vasodilation in conduit arteries). We genotyped 25 common SNPs in the ESR1 gene, and related them to EDV and FMD using multivariable linear regression, adjusting for sex and other potential confounders, such as major cardiovascular risk factors and medications. Haplotypes were estimated using the PHASE software.

    RESULTS:

    We observed an association between rs1709183 in the ESR1 gene and EDV (nominal P=0.0012), with a lower EDV in carriers of the minor allele (C). This association remained significant after adjustment for multiple testing (empirical P=0.031, obtained using bootstrap re-sampling). Two ESR1 haplotypes in the block containing rs1709183 were associated with EDV (individual haplotype P=0.0015 and P=0.025); the directions of effect were consistent with individual SNP analyses. FMD was not associated with any of the ESR1 SNPs.

    CONCLUSIONS:

    In our community-based study of elderly, a polymorphism in the estrogen receptor alpha gene was associated with endothelium-dependent vasodilation in resistance, but not conduit arteries. Our findings should stimulate further exploration in other settings.

  • 103.
    Ingelsson, Erik
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Yin, Li
    Bäck, Magnus
    Nationwide cohort study of the leukotriene receptor antagonist montelukast and incident or recurrent cardiovascular disease2012Inngår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 129, nr 3, s. 702-707.e2Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The leukotriene pathway has been associated with an increased cardiovascular risk. However, the effects of the antileukotriene treatment used in asthmatic patients on cardiovascular outcomes have remained largely unexplored.

    OBJECTIVE: We sought to examine a potential protective role of the leukotriene receptor antagonist montelukast on future risk of incident and recurrent myocardial infarction and ischemic stroke.

    METHODS: A nationwide population-based cohort of approximately 7 million persons integrating data from the Prescribed Drug, Patient, Cause of Death, Income, Educational, and Emigration Registers was followed from July 1, 2005, to December 31, 2008. Analyses were performed in the whole population after exclusion of subjects with a prior cardiovascular diagnosis (incident events; sample size, n = 6,910,923 for myocardial infarction and n = 6,932,578 for stroke) and in subjects with a prior diagnosis (recurrent events; n = 153,937 and n = 132,291 for stroke and myocardial infarction, respectively).

    RESULTS: Cox proportional hazard ratios (HRs) did not reveal an association of montelukast use with incident events. In contrast to these findings, montelukast use was associated with a lower risk for recurrent stroke (HR, 0.62; 95% CI, 0.38-0.99) accounting for age, sex, education level, and yearly income. Adjusting the latter finding also for respiratory and cardiovascular medications and diagnoses revealed similar point estimates (HR, 0.62; 95% CI, 0.39-1.0). Post hoc analyses revealed a significant association of montelukast use with a lower risk for recurrent myocardial infarction in male subjects (HR, 0.65; 95% CI, 0.43-0.99).

    CONCLUSION: These data provide a first indication for a potential role of the antiasthma drug montelukast for secondary prevention of cardiovascular disease.

  • 104.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Inflammation, as measured by the erythrocyte sedimentation rate, is an independent predictor for the development of heart failure2005Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 45, nr 11, s. 1802-1806Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Our objective was to explore inflammation, measured as erythrocyte sedimentation rate (ESR), as a predictor for the development of heart failure (HF).

    BACKGROUND: In recent years, evidence of the importance of inflammation in the pathophysiology of HF has emerged, and various inflammatory markers have been found to predict future HF. Erythrocyte sedimentation rate is an inexpensive and easily accessible marker of systemic inflammation, but to this date it is unknown whether ESR predicts subsequent HF.

    METHODS: In a community-based prospective study of 2,314 middle-aged men free from HF, myocardial infarction, and valvular disease at baseline, ESR was analyzed in multivariable models together with established risk factors for HF (hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, obesity, and serum cholesterol) and hematocrit.

    RESULTS: A total of 282 men developed HF during a median follow-up time of 30 years. In Cox proportional hazards analyses, ESR was an independent predictor of HF (hazard ratio 1.46 for highest quartile vs. the lowest, 95% confidence interval 1.04 to 2.06). This observation remained significant when also adjusting for interim myocardial infarction during follow-up.

    CONCLUSIONS: Erythrocyte sedimentation rate was a significant predictor of HF, independent of established risk factors for HF, and interim myocardial infarction after three decades of follow-up in a population-based sample of middle-aged men. Our findings indicate that inflammation occurs early in the process leading to HF and that ESR could be used to evaluate this process.

  • 105.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    The validity of a diagnosis of heart failure in a hospital discharge register2005Inngår i: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 7, nr 5, s. 787-791Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND AIMS: The accuracy of a diagnosis of heart failure (HF) in hospital discharge registers is largely unknown. We aimed to determine the validity of such a diagnosis in the Swedish hospital discharge register.

    METHODS AND RESULTS: In a population-based study of 2322 middle-aged men (the ULSAM study), 321 participants were diagnosed with HF according to the Swedish hospital discharge register, during a median follow-up time of 29 years. A review board examined the validity of the diagnosis according to the European Society of Cardiology definition of HF. Eighty-two percent of the possible cases were classified as having definite HF. An echocardiographic examination increased the validity to 88%. For patients treated at an internal medicine or cardiology clinic the validity was 86% and 91%, respectively. If HF was the primary diagnosis, the validity was 95%, irrespective of clinic type.

    CONCLUSION: The HF diagnosis in the Swedish hospital discharge register appears slightly less precise than for acute myocardial infarction and stroke. For population-based research, only those with a primary diagnosis of HF in the hospital discharge register should be regarded as definite HF cases, or alternatively the cases should be validated individually.

  • 106.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Relative importance and conjoint effects of obesity and physical inactivity for the development of insulin resistance2009Inngår i: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 16, nr 1, s. 28-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Obesity and physical inactivity are related to the development of insulin resistance, but their relative importance and conjoint effects are unclear. METHODS: We related body mass index (BMI) and self-reported leisure-time physical activity (PA) at the age of 50 years to insulin sensitivity measured with euglycemic insulin clamp technique and the presence of metabolic syndrome (MetS) at a subsequent examination, 20 years later, in 862 men free from diabetes and MetS at baseline. RESULTS: In a multivariable model including BMI, PA, homeostasis model assessment insulin resistance index, erythrocyte sedimentation rate, and all components of MetS at baseline, both BMI (beta, -0.19 mg/kg bodyweight/min per 1 kg/m; P<0.0001) and PA (adjusted least square means, 5.1, 5.2, 5.4, and 6.2 mg/kg bodyweight/min in individuals with sedentary, moderate, regular, and athletic PA, respectively; P=0.0035) were significant predictors of insulin sensitivity at age 70. When categorizing individuals into four groups by BMI and PA at baseline, insulin sensitivity at the age of 70 years decreased significantly over the following categories: multivariable-adjusted least square means, 5.8 (low BMI/high PA); 5.6 (low BMI/low PA); 5.1 (high BMI/high PA); and 4.6 (high BMI/low PA) mg/kg bodyweight/min, respectively; P value of less than 0.0001. CONCLUSION: In our community-based sample of middle-aged men, BMI and PA were independent predictors of insulin resistance after 20 years of follow-up. Our results imply that obesity and physical inactivity may increase insulin resistance and metabolic risk by partly independent pathways, and emphasize the importance of strategies that address both obesity and physical inactivity to achieve increased public health.

  • 107.
    Ingelsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Vessby, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Enheten för klinisk näringsforskning.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Novel metabolic risk factors for heart failure2005Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 46, nr 11, s. 2054-2060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Our objectives were to explore novel metabolic risk factors for development of heart failure (HF).

    BACKGROUND: In the past decade, considerable knowledge has been gained from limited samples regarding novel risk factors for HF, but the importance of these in the general population is largely unexplored.

    METHODS: In a community-based prospective study of 2,321 middle-aged men free from HF and valvular disease at baseline, variables reflecting glucose and lipid metabolism and variables involved in oxidative processes were compared with established risk factors for HF (prior myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, obesity, and serum cholesterol) using Cox proportional hazards analyses.

    RESULTS: During a median follow-up time of 29 years, 259 subjects developed HF. In a multivariable Cox proportional hazards backward stepwise model, a 1-SD increase of fasting proinsulin (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.15 to 1.66) and apolipoprotein B/A-I-ratio (HR 1.27, 95% CI 1.09 to 1.48) increased the risk, whereas a 1-SD increase in serum beta-carotene (HR 0.79, 95% CI 0.66 to 0.94) decreased the risk of HF. These variables also remained significant when adjusting for acute myocardial infarction during follow-up.

    CONCLUSIONS: Novel variables reflecting insulin resistance and dyslipidemia, together with a low beta-carotene level, were found to predict HF independently of established risk factors. If confirmed, our observations could have large clinical implications, as they may offer new approaches in the prevention of HF.

  • 108.
    Jiang, Xia
    et al.
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA.;Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Nobels Vagen 13, S-17177 Stockholm, Sweden..
    O'Reilly, Paul F.
    Kings Coll London, Inst Psychiat, Dept Social Genet & Dev Psychiat, De Crespigny Pk, London SE5 8AF, England..
    Aschard, Hugues
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA.;Inst Pasteur, Ctr Bioinformat Biostat & Biol Integrat C3BI, F-75724 Paris, France..
    Hsu, Yi-Hsiang
    Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA 02142 USA..
    Richards, J. Brent
    Dept Med, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.;Dept Human Genet, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.;Dept Epidemiol, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.;Dept Biostat, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada..
    Dupuis, Josee
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, USA.
    Karasik, David
    Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA..
    Pilz, Stefan
    Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Auenbruggerpl 15, A-8036 Graz, Austria..
    Berry, Diane
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England..
    Kestenbaum, Bryan
    Kidney Res Inst, Div Nephrol, 325 Ninth Ave, Seattle, WA 98104 USA..
    Zheng, Jusheng
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Luan, Jianan
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Sofianopoulou, Eleni
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England..
    Streeten, Elizabeth A.
    Univ Maryland, Genet & Personalized Med Program, Sch Med, Howard Hall Room 567, Baltimore, MD 21201 USA..
    Albanes, Demetrius
    NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Lutsey, Pamela L.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA..
    Yao, Lu
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA..
    Tang, Weihong
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA..
    Econs, Michael J.
    Indiana Univ, Dept Med, Endocrinol, 1120W Michigan St, Indianapolis, IN 46202 USA..
    Wallaschofski, Henri
    Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17489 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, D-13316 Greifswald, Germany..
    Voelzke, Henry
    DZHK German Ctr Cardiovasc Res, Partner Site, D-13316 Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, SHIP Klinisch Epidemiol Forsch, Walther Rathenau Str 48, D-17475 Greifswald, Germany..
    Zhou, Ang
    Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia..
    Power, Chris
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England..
    McCarthy, Mark I.
    Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England.;Univ Oxford, Wellcome Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.;Churchill Hosp, Oxford NIHR Biomed Res Ctr, Old Rd, Oxford OX3 7LJ, England..
    Michos, Erin D.
    Johns Hopkins Sch Med, Ciccarone Ctr Prevent Heart Dis, Div Cardiol, Baltimore, MD 21287 USA.;Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA..
    Weinstein, Stephanie J.
    NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Freedman, Neal D.
    NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Huang, Wen-Yi
    NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Van Schoor, Natasja M.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam Publ Hlth Res Inst, Boelelaan 1089a, NL-1081 HV Amsterdam, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands.;AMC, Internal Med, Dept Geriatr, POB 22700, NL-1100 DE Amsterdam, Netherlands..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Dept Human Nutr, POB 176700, NL-700 AA Wageningen, Netherlands..
    Enneman, Anke
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Cupples, L. Adrienne
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA..
    Booth, Sarah L.
    Tufts Univ, Vitamin K Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA..
    Vasan, Ramachandran S.
    Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA..
    Liu, Ching-Ti
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA..
    Zhou, Yanhua
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA..
    Ripatti, Samuli
    Univ Helsinki, Stat & Translat Genet, Biomedicum, Tukholmankatu 8, Helsinki 2U, Finland..
    Ohlsson, Claes
    Univ Gothenburg, Dept Internal Med & Clin Nutr, Vita Straket 11, S-41345 Gothenburg, Sweden..
    Vandenput, Liesbeth
    Univ Gothenburg, Dept Internal Med & Clin Nutr, Vita Straket 11, S-41345 Gothenburg, Sweden..
    Lorentzon, Mattias
    Univ Gothenburg, Dept Geriatr Med, S-43180 Molndal, Sweden.;Sahlgrens Univ Hosp, S-43180 Molndal, Sweden..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, POB 20,Tukholmankatu 8 B, FIN-00014 Helsinki, Finland.;Univ Helsinki, Helsinki Univ Hosp, POB 20,Tukholmankatu 8 B, FIN-00014 Helsinki, Finland.;Univ Helsinki, Folkhalsan Res Ctr, POB 2000014, Helsinki, Finland..
    Shea, M. Kyla
    Tufts Univ, Vitamin K Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA..
    Houston, Denise K.
    Wake Forest Sch Med, Sticht Ctr Healthy Aging & Alzheimers Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Kritchevsky, Stephen B.
    Wake Forest Sch Med, Sticht Ctr Healthy Aging & Alzheimers Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Liu, Yongmei
    Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Lohman, Kurt K.
    Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Ferrucci, Luigi
    NIA, Longitudinal Studies Sect, Intramural Res Program, NIH, Baltimore, MD 21225 USA..
    Peacock, Munro
    Indiana Univ, Dept Med, Endocrinol, 1120W Michigan St, Indianapolis, IN 46202 USA..
    Gieger, Christian
    German Res Ctr Environm Hlth, Mol Epidemiol, AME, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany..
    Beekman, Marian
    Leiden Univ, Mol Epidemiol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands..
    Slagboom, Eline
    Leiden Univ, Mol Epidemiol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands..
    Deelen, Joris
    Leiden Univ, Mol Epidemiol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands.;Max Planck Inst Biol Ageing, Joseph Stelzmann Str 9b, D-50931 Cologne, Germany..
    van Heemst, Diana
    Leiden Univ, Gerontol & Geriatr, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, Theodor Kutzer Ufer1, D-68167 Mannheim, Germany..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, Theodor Kutzer Ufer1, D-68167 Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Auenbruggerpl 15, A-8036 Graz, Austria.;SYNLAB Holding Deutschland GmbH, Gubener Str 39, D-86156 Augsburg, Germany..
    de Boer, Ian H.
    Univ Washington, Div Nephrol, 325 Ninth Ave, Washington, DC 98104 USA.;Univ Washington, Kidney Res Inst, 325 Ninth Ave, Washington, DC 98104 USA..
    Wood, Alexis C.
    ARS, USDA, Childrens Nutr Res Ctr, 1100 Bates Ave, Houston, TX 77071 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Rich, Stephen S.
    Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA..
    Robinson-Cohen, Cassianne
    Vanderbilt Univ, Div Nephrol, Dept Med, Med Ctr, 1161 21st Ave S, Nashville, TN 37232 USA..
    den Heijer, Martin
    Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Epidemiol & Biostat Sch Publ Hlth, 156 Norfolk Pl,St Marys Campus, London W2 1PG, England.;Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Univ Oulu, Bioctr Oulu, POB 5000,Aapistie 5A, FI-90014 Oulu, Finland.;Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50 POB 20,90029 OYS, FI-90220 Oulu, Finland..
    Cavadino, Alana
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England.;Queen Mary Univ London, Ctr Environm & Prevent Med, Wolfson Inst Prevent Med, Barts & London Sch Med & Dent, Charterhouse Sq, London EC1M 6BQ, England..
    Joshi, Peter K.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland..
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, MRC Inst Genet Mol Med, Western Gen Hosp, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Hayward, Caroline
    Univ Edinburgh, MRC Inst Genet Mol Med, Western Gen Hosp, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Trompet, Stella
    Leiden Univ, Gerontol & Geriatr, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Dept Cardiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Rivadeneira, Fernando
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Broer, Linda
    Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Zgaga, Lina
    Univ Dublin, Trinity Coll Dublin, Dept Publ Hlth & Primary Care, Inst Populat Hlth, D02 PN40, Dublin 24, Ireland..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Theodoratou, Evropi
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Farrington, Susan M.
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Timofeeva, Maria
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Dunlop, Malcolm G.
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Valdes, Ana M.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus,Westminster Bridge Rd, London SE1 7EH, England.;Univ Nottingham, Sch Med, City Hosp, Hucknall Rd, Nottingham NG5 1PB, England..
    Tikkanen, Emmi
    Univ Helsinki, FIMM Inst Mol Med Finland, POB 20, FI-00014 Helsinki, Finland..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Dept Clin Physiol, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20014, Finland..
    Mikkila, Vera
    Acad Finland, Hakaniemenranta 6,POB 131, FI-00531 Helsinki, Finland..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Sattar, Naveed
    BHF Glasgow Cardiovasc Res Ctr, Fac Med, Univ Ave, Glasgow G12 8QQ, Lanark, Scotland..
    Jukema, J. Wouter
    Leiden Univ, Dept Cardiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Einthoven Lab Expt Vasc Med, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands..
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Langenberg, Claudia
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Forouhi, Nita G.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Gundersen, Thomas E.
    Vitas AS, Gaustadaleen 21, N-0349 Oslo, Norway..
    Khaw, Kay-Tee
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England..
    Butterworth, Adam S.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England..
    Danesh, John
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England.;Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Spector, Timothy
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus,Westminster Bridge Rd, London SE1 7EH, England..
    Wang, Thomas J.
    Vanderbilt Heart & Vasc Inst, Div Cardiovasc Med, 2220 Pierce Ave 383 Preston Res Bldg, Nashville, TN 37232 USA..
    Hypponen, Elina
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England.;Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia..
    Kraft, Peter
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA..
    Kiel, Douglas P.
    Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA 02142 USA..
    Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels2018Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, artikkel-id 260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

  • 109.
    Jobs, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Adamsson, Viola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Jobs, Magnus
    Nerpin, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Influence of a prudent diet on circulating cathepsin S in humans2014Inngår i: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 13, s. 84-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Increased circulating cathepsin S levels have been linked to increased risk of cardiometabolic diseases and cancer. However, whether cathepsin S is a modifiable risk factor is unclear. We aimed to investigate the effects of a prudent diet on plasma cathepsin S levels in healthy individuals. Findings: Explorative analyses of a randomized study were performed in 88 normal to slightly overweight and hyperlipidemic men and women (aged 25 to 65) that were randomly assigned to ad libitum prudent diet, i.e. healthy Nordic diet (ND) or a control group (habitual Western diet) for 6 weeks. Whereas all foods in the ND were provided, the control group was advised to consume their habitual diet throughout the study. The ND was in line with dietary recommendations, e. g. low in saturated fats, sugars and salt, but high in plant-based foods rich in fibre and unsaturated fats. The ND significantly decreased cathepsin S levels (from 20.1 (+/-4.0 SD) to 19.7 mu g/L (+/-4.3 SD)) compared with control group (from 18.2 (+/-2.9 SD) to 19.1 mu g/L (+/-3.8 SD)). This difference remained after adjusting for sex and change in insulin sensitivity (P = 0.03), and near significant after adjusting for baseline cathepsin S levels (P = 0.06), but not for change in weight or LDL-C. Changes in cathepsin S levels were directly correlated with change in LDL-C. Conclusions: Compared with a habitual control diet, a provided ad libitum healthy Nordic diet decreased cathepsin S levels in healthy individuals, possibly mediated by weight loss or lowered LDL-C. These differences between groups in cathepsin S were however not robust and therefore need further investigation.

  • 110.
    Jobs, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Nerpin, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Jobs, Magnus
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Association Between Serum Cathepsin S and Mortality in Older Adults2011Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 306, nr 10, s. 1113-1121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Experimental data suggest that cathepsin S, a cysteine protease, is involved in the complex pathways leading to cardiovascular disease and cancer. However, prospective data concerning a potential association between circulating cathepsin S levels and mortality are lacking.

    Objective: To investigate associations between circulating cathepsin S levels and mortality in 2 independent cohorts of elderly men and women.

    Design, Setting, and Participants: Prospective study using 2 community-based cohorts, the Uppsala Longitudinal Study of Adult Men (ULSAM; n=1009; mean age: 71 years; baseline period: 1991-1995; median follow-up: 12.6 years; end of follow-up: 2006) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n=987; 50% women; mean age: 70 years; baseline period: 2001-2004; median follow-up: 7.9 years; end of follow-up: 2010). Serum samples were used to measure cathepsin S.

    Main Outcome Measure: Total mortality.

    Results: During follow-up, 413 participants died in the ULSAM cohort (incidence rate: 3.59/100 person-years at risk) and 100 participants died in the PIVUS cohort (incidence rate: 1.32/100 person-years at risk). In multivariable Cox regression models adjusted for age, systolic blood pressure, diabetes, smoking status, body mass index, total cholesterol, high-density lipoprotein cholesterol, antihypertensive treatment, lipid-lowering treatment, and history of cardiovascular disease, higher serum cathepsin S was associated with an increased risk for mortality (ULSAM cohort: hazard ratio [HR] for 1-unit increase of cathepsin S, 1.04 [95% CI, 1.01-1.06], P=.009; PIVUS cohort: HR for 1-unit increase of cathepsin S, 1.03 [95% CI, 1.00-1.07], P=.04). In the ULSAM cohort, serum cathepsin S also was associated with cardiovascular mortality (131 deaths; HR for quintile 5 vs quintiles 1-4, 1.62 [95% CI, 1.11-2.37]; P=.01) and cancer mortality (148 deaths; HR for 1-unit increase of cathepsin S, 1.05 [95% CI, 1.01-1.10]; P=.01).

    Conclusions: Among elderly individuals in 2 independent cohorts, higher serum cathepsin S levels were associated with increased mortality risk. Additional research is needed to delineate the role of cathepsin S and whether its measurement might have clinical utility.

  • 111.
    Jobs, Elisabeth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Jobs, Magnus
    University of Dalarna.
    Nerpin, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Iggman, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Oxidativ stress och inflammation.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lars, Lind
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men2013Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 1, s. 163-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

    RESEARCH DESIGN AND METHODS:

    Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

    RESULTS:

    After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).

    CONCLUSIONS:

    Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.

  • 112. Joshi, Peter K
    et al.
    Esko, Tonu
    Mattsson, Hannele
    Eklund, Niina
    Gandin, Ilaria
    Nutile, Teresa
    Jackson, Anne U
    Schurmann, Claudia
    Smith, Albert V
    Zhang, Weihua
    Okada, Yukinori
    Stančáková, Alena
    Faul, Jessica D
    Zhao, Wei
    Bartz, Traci M
    Concas, Maria Pina
    Franceschini, Nora
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Vitart, Veronique
    Trompet, Stella
    Guo, Xiuqing
    Chasman, Daniel I
    O'Connel, Jeffrey R
    Corre, Tanguy
    Nongmaithem, Suraj S
    Chen, Yuning
    Mangino, Massimo
    Ruggiero, Daniela
    Traglia, Michela
    Farmaki, Aliki-Eleni
    Kacprowski, Tim
    Bjonnes, Andrew
    van der Spek, Ashley
    Wu, Ying
    Giri, Anil K
    Yanek, Lisa R
    Wang, Lihua
    Hofer, Edith
    Rietveld, Cornelius A
    McLeod, Olga
    Cornelis, Marilyn C
    Pattaro, Cristian
    Verweij, Niek
    Baumbach, Clemens
    Abdellaoui, Abdel
    Warren, Helen R
    Vuckovic, Dragana
    Mei, Hao
    Bouchard, Claude
    Perry, John R B
    Cappellani, Stefania
    Mirza, Saira S
    Benton, Miles C
    Broeckel, Ulrich
    Medland, Sarah E
    Lind, Penelope A
    Malerba, Giovanni
    Drong, Alexander
    Yengo, Loic
    Bielak, Lawrence F
    Zhi, Degui
    van der Most, Peter J
    Shriner, Daniel
    Mägi, Reedik
    Hemani, Gibran
    Karaderi, Tugce
    Wang, Zhaoming
    Liu, Tian
    Demuth, Ilja
    Zhao, Jing Hua
    Meng, Weihua
    Lataniotis, Lazaros
    van der Laan, Sander W
    Bradfield, Jonathan P
    Wood, Andrew R
    Bonnefond, Amelie
    Ahluwalia, Tarunveer S
    Hall, Leanne M
    Salvi, Erika
    Yazar, Seyhan
    Carstensen, Lisbeth
    de Haan, Hugoline G
    Abney, Mark
    Afzal, Uzma
    Allison, Matthew A
    Amin, Najaf
    Asselbergs, Folkert W
    Bakker, Stephan J L
    Barr, R Graham
    Baumeister, Sebastian E
    Benjamin, Daniel J
    Bergmann, Sven
    Boerwinkle, Eric
    Bottinger, Erwin P
    Campbell, Archie
    Chakravarti, Aravinda
    Chan, Yingleong
    Chanock, Stephen J
    Chen, Constance
    Chen, Y-D Ida
    Collins, Francis S
    Connell, John
    Correa, Adolfo
    Cupples, L Adrienne
    Smith, George Davey
    Davies, Gail
    Dörr, Marcus
    Ehret, Georg
    Ellis, Stephen B
    Feenstra, Bjarke
    Feitosa, Mary F
    Ford, Ian
    Fox, Caroline S
    Frayling, Timothy M
    Friedrich, Nele
    Geller, Frank
    Scotland, Generation
    Gillham-Nasenya, Irina
    Gottesman, Omri
    Graff, Misa
    Grodstein, Francine
    Gu, Charles
    Haley, Chris
    Hammond, Christopher J
    Harris, Sarah E
    Harris, Tamara B
    Hastie, Nicholas D
    Heard-Costa, Nancy L
    Heikkilä, Kauko
    Hocking, Lynne J
    Homuth, Georg
    Hottenga, Jouke-Jan
    Huang, Jinyan
    Huffman, Jennifer E
    Hysi, Pirro G
    Ikram, M Arfan
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Joensuu, Anni
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jousilahti, Pekka
    Jukema, J Wouter
    Kähönen, Mika
    Kamatani, Yoichiro
    Kanoni, Stavroula
    Kerr, Shona M
    Khan, Nazir M
    Koellinger, Philipp
    Koistinen, Heikki A
    Kooner, Manraj K
    Kubo, Michiaki
    Kuusisto, Johanna
    Lahti, Jari
    Launer, Lenore J
    Lea, Rodney A
    Lehne, Benjamin
    Lehtimäki, Terho
    Liewald, David C M
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Loh, Marie
    Lokki, Marja-Liisa
    London, Stephanie J
    Loomis, Stephanie J
    Loukola, Anu
    Lu, Yingchang
    Lumley, Thomas
    Lundqvist, Annamari
    Männistö, Satu
    Marques-Vidal, Pedro
    Masciullo, Corrado
    Matchan, Angela
    Mathias, Rasika A
    Matsuda, Koichi
    Meigs, James B
    Meisinger, Christa
    Meitinger, Thomas
    Menni, Cristina
    Mentch, Frank D
    Mihailov, Evelin
    Milani, Lili
    Montasser, May E
    Montgomery, Grant W
    Morrison, Alanna
    Myers, Richard H
    Nadukuru, Rajiv
    Navarro, Pau
    Nelis, Mari
    Nieminen, Markku S
    Nolte, Ilja M
    O'Connor, George T
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R
    Pankow, James S
    Patarcic, Inga
    Pavani, Francesca
    Peyser, Patricia A
    Pietilainen, Kirsi
    Poulter, Neil
    Prokopenko, Inga
    Ralhan, Sarju
    Redmond, Paul
    Rich, Stephen S
    Rissanen, Harri
    Robino, Antonietta
    Rose, Lynda M
    Rose, Richard
    Sala, Cinzia
    Salako, Babatunde
    Salomaa, Veikko
    Sarin, Antti-Pekka
    Saxena, Richa
    Schmidt, Helena
    Scott, Laura J
    Scott, William R
    Sennblad, Bengt
    Seshadri, Sudha
    Sever, Peter
    Shrestha, Smeeta
    Smith, Blair H
    Smith, Jennifer A
    Soranzo, Nicole
    Sotoodehnia, Nona
    Southam, Lorraine
    Stanton, Alice V
    Stathopoulou, Maria G
    Strauch, Konstantin
    Strawbridge, Rona J
    Suderman, Matthew J
    Tandon, Nikhil
    Tang, Sian-Tsun
    Taylor, Kent D
    Tayo, Bamidele O
    Töglhofer, Anna Maria
    Tomaszewski, Maciej
    Tšernikova, Natalia
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Vaidya, Dhananjay
    van Hylckama Vlieg, Astrid
    van Setten, Jessica
    Vasankari, Tuula
    Vedantam, Sailaja
    Vlachopoulou, Efthymia
    Vozzi, Diego
    Vuoksimaa, Eero
    Waldenberger, Melanie
    Ware, Erin B
    Wentworth-Shields, William
    Whitfield, John B
    Wild, Sarah
    Willemsen, Gonneke
    Yajnik, Chittaranjan S
    Yao, Jie
    Zaza, Gianluigi
    Zhu, Xiaofeng
    Salem, Rany M
    Melbye, Mads
    Bisgaard, Hans
    Samani, Nilesh J
    Cusi, Daniele
    Mackey, David A
    Cooper, Richard S
    Froguel, Philippe
    Pasterkamp, Gerard
    Grant, Struan F A
    Hakonarson, Hakon
    Ferrucci, Luigi
    Scott, Robert A
    Morris, Andrew D
    Palmer, Colin N A
    Dedoussis, George
    Deloukas, Panos
    Bertram, Lars
    Lindenberger, Ulman
    Berndt, Sonja I
    Lindgren, Cecilia M
    Timpson, Nicholas J
    Tönjes, Anke
    Munroe, Patricia B
    Sørensen, Thorkild I A
    Rotimi, Charles N
    Arnett, Donna K
    Oldehinkel, Albertine J
    Kardia, Sharon L R
    Balkau, Beverley
    Gambaro, Giovanni
    Morris, Andrew P
    Eriksson, Johan G
    Wright, Margie J
    Martin, Nicholas G
    Hunt, Steven C
    Starr, John M
    Deary, Ian J
    Griffiths, Lyn R
    Tiemeier, Henning
    Pirastu, Nicola
    Kaprio, Jaakko
    Wareham, Nicholas J
    Pérusse, Louis
    Wilson, James G
    Girotto, Giorgia
    Caulfield, Mark J
    Raitakari, Olli
    Boomsma, Dorret I
    Gieger, Christian
    van der Harst, Pim
    Hicks, Andrew A
    Kraft, Peter
    Sinisalo, Juha
    Knekt, Paul
    Johannesson, Magnus
    Magnusson, Patrik K E
    Hamsten, Anders
    Schmidt, Reinhold
    Borecki, Ingrid B
    Vartiainen, Erkki
    Becker, Diane M
    Bharadwaj, Dwaipayan
    Mohlke, Karen L
    Boehnke, Michael
    van Duijn, Cornelia M
    Sanghera, Dharambir K
    Teumer, Alexander
    Zeggini, Eleftheria
    Metspalu, Andres
    Gasparini, Paolo
    Ulivi, Sheila
    Ober, Carole
    Toniolo, Daniela
    Rudan, Igor
    Porteous, David J
    Ciullo, Marina
    Spector, Tim D
    Hayward, Caroline
    Dupuis, Josée
    Loos, Ruth J F
    Wright, Alan F
    Chandak, Giriraj R
    Vollenweider, Peter
    Shuldiner, Alan R
    Ridker, Paul M
    Rotter, Jerome I
    Sattar, Naveed
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    North, Kari E
    Pirastu, Mario
    Psaty, Bruce M
    Weir, David R
    Laakso, Markku
    Gudnason, Vilmundur
    Takahashi, Atsushi
    Chambers, John C
    Kooner, Jaspal S
    Strachan, David P
    Campbell, Harry
    Hirschhorn, Joel N
    Perola, Markus
    Polašek, Ozren
    Wilson, James F
    Directional dominance on stature and cognition in diverse human populations2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 523, nr 7561, s. 459-462Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

  • 113. Justice, Anne E.
    et al.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Wallentin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Lindgren, Cecilia M.
    Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution2019Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, nr 3, s. 452-469Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

  • 114.
    Justice, Anne E.
    et al.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Winkler, Thomas W.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    Graff, Misa
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Fisher, Virginia A.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Young, Kristin
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Barata, Llilda
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    Deng, Xuan
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Czajkowski, Jacek
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    Hadley, David
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.;TransMed Syst Inc, Cupertino, CA 95014 USA..
    Ngwa, Julius S.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA..
    Ahluwalia, Tarunveer S.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Steno Diabet Ctr, Gentofte, Denmark..
    Chu, Audrey Y.
    NHLBI Framingham Heart Study, Framingham, MA 01702 USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Heard-Costa, Nancy L.
    NHLBI Framingham Heart Study, Framingham, MA 01702 USA.;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA..
    Lim, Elise
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Perez, Jeremiah
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Eicher, John D.
    Framingham Heart Dis Epidemiol Study, NIH, Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA..
    Kutalik, Zoltan
    CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland.;Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Xue, Luting
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Renstrom, Frida
    Umea Univ, Dept Biobank Res, Umea, Sweden.;Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden..
    Wu, Joseph
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Qi, Qibin
    Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA..
    Ahmad, Shafqat
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Alfred, Tamuno
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA..
    Amin, Najaf
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands..
    Bielak, Lawrence F.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Bonnefond, Amelie
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Bragg, Jennifer
    Univ Michigan, Internal Med Nephrol, Ann Arbor, MI USA.;Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Cadby, Gemma
    Univ Western Australia, Ctr Genet Origins Hlth & Dis, Crawley 6009, Australia..
    Chittani, Martina
    Univ Milan, Dept Hlth Sci, Via A Di Rudini 8, I-20142 Milan, Italy..
    Coggeshall, Scott
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Corre, Tanguy
    CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland.;Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Direk, Nese
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Dokuz Eylul Univ, Dept Psychiat, Izmir, Turkey..
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Gorski, Mathias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Harder, Marie Neergaard
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Horikoshi, Momoko
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England..
    Huang, Tao
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Epidemiol Domain, Singapore 117549, Singapore..
    Huffman, Jennifer E.
    Framingham Heart Dis Epidemiol Study, NIH, Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA.;Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Kinnunen, Leena
    Natl Inst Hlth & Welfare, Dept Hlth, FI-00271 Helsinki, Finland..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Komulainen, Pirjo
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Kumari, Meena
    Univ Essex, ISER, Colchester CO4 3SQ, Essex, England.;UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Lim, Unhee
    Univ Hawaii, Canc Ctr, Epidemiol Program, Honolulu, HI 96813 USA..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere 33014, Finland..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England..
    Manichaikul, Ani
    Univ Virginia, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22903 USA.;Univ Virginia, Dept Publ Hlth Sci, Biostat Sect, Charlottesville, VA 22903 USA..
    Marten, Jonathan
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Middelberg, Rita P. S.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Navarro, Pau
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Perusse, Louis
    Univ Laval, Fac Med, Dept Kinesiol, Quebec City G1V 0A6, PQ, Canada.;Univ Laval, Inst Nutr & Funct Foods, Quebec City G1V 0A6, PQ, Canada..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, EE-51010 Tartu, Estonia..
    Sarti, Cinzia
    Dept Social & Hlth Care, Helsinki, Finland..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Smith, Jennifer A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Stancakova, Alena
    Univ Eastern Finland, Inst Clin Med, Dept Med, Kuopio 70210, Finland..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Sung, Yun Ju
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Tanaka, Toshiko
    Natl Inst Aging, Translat Gerontol Branch, Baltimore, MD USA..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Trompet, Stella
    Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    van der Laan, Sander W.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Vedantam, Sailaja L.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Vink, Jacqueline M.
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands.;Radboud Univ Nijmegen, Behav Sci Inst, Nijmegen, Netherlands..
    Vitart, Veronique
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Wu, Ying
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Yengo, Loic
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Zhang, Weihua
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Zimmermann, Martina E.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Zubair, Niha
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Adair, Linda S.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA..
    Afaq, Saima
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England..
    Afzal, Uzma
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England..
    Bakker, Stephan J. L.
    Univ Med Ctr Groningen, Univ Groningen, Dept Med, Groningen, Netherlands..
    Bartz, Traci M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Beilby, John
    Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia.;Sir Charles Gairdner Hosp, PathWest Lab Med WA, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Pathol, 35 Stirling Hwy, Crawley, WA 6009, Australia.;Univ Western Australia, Laboraty Med, 35 Stirling Hwy, Crawley, WA 6009, Australia..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Bergmann, Sven
    Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Biffar, Reiner
    Univ Med Greifswald, Clin Prosthet Dent Gerostomatol & Mat Sci, Greifswald, Germany..
    Blangero, John
    Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr, Human Genet Ctr, POB 20186, Houston, TX 77225 USA..
    Bonnycastle, Lori L.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Bottinger, Erwin
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY USA..
    Braga, Daniele
    Univ Milan, Dept Hlth Sci, Via A Di Rudini 8, I-20142 Milan, Italy..
    Buckley, Brendan M.
    Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland..
    Buyske, Steve
    Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA.;Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Chambers, John C.
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Collins, Francis S.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    de Borst, Gert J.
    UMC Utrecht, Dept Vasc Surg, Div Surg Specialties, Utrecht, Netherlands..
    de Craen, Anton J. M.
    Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    de Geus, Eco J. C.
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ, FMGO Inst, Amsterdam, Netherlands.;Vrije Univ, Med Ctr, Amsterdam, Netherlands..
    Dedoussis, George
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Delgado, Graciela E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    den Ruijter, Hester M.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    Eiriksdottir, Gudny
    Iceland Heart Assoc, Kopavogur, Iceland..
    Eriksson, Anna L.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA..
    Faul, Jessica D.
    Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48109 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Forrester, Terrence
    Univ West Indies, Trop Med Res Inst, Trop Metab Res Unit, Mona JMAAW15, Jamaica, NY USA..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Glorioso, Nicola
    Univ Sassari, Hypertens & Related Dis Ctr, AOU, Sassari, Italy..
    Gong, Jian
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Grallert, Harald
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Grammer, Tanja B.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Haitjema, Saskia
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    Hallmans, Goran
    Umea Univ, Sect Nutr Res, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Hansen, Torben
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England..
    Harris, Tamara B.
    Natl Inst Aging, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Hassinen, Maija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Hastie, Nicholas D.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Heath, Andrew C.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Hernandez, Dena
    Natl Inst Aging, Lab Neurogenet, Bethesda, MD USA..
    Hindorff, Lucia
    Natl Human Genome Res Inst, NIH, Div Genom Med, Bethesda, MD 20892 USA..
    Hocking, Lynne J.
    Univ Aberdeen, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Holmen, Oddgeir L.
    Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany..
    Hottenga, Jouke Jan
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands..
    Huang, Jie
    Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England..
    Hung, Joseph
    Univ Western Australia, Sch Med & Pharmacol, 25 Stirling Hwy, Crawley, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Cardiovasc Med, Nedlands, WA 6009, Australia..
    Hutri-Kahonen, Nina
    Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Pediat, Tampere 33014, Finland..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    James, Alan L.
    Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Med & Pharmacol, 25 Stirling Hwy, Crawley, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia..
    Jansson, John-Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Norfolk Pl, London, England.;Univ Oulu, Fac Med, Ctr Life Course Epidemiol, POB 5000, FI-90014 Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50,POB 20, FI-90220 Oulu, Finland..
    Jhun, Min A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Juonala, Markus
    Univ Turku, Dept Med, Turku 20520, Finland.;Turku Univ Hosp, Div Med, Turku 20521, Finland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Physiol, Tampere 33014, Finland..
    Karlsson, Magnus
    Lund Univ, Skane Univ Hosp, Dept Orthoped & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welfare, Dept Hlth, FI-00271 Helsinki, Finland.;Univ Helsinki, Endocrinol, Dept Med, FI-00029 Helsinki, Finland.;Univ Helsinki, Endocrinol, Abdominal Ctr, FI-00029 Helsinki, Finland.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland.;Minerva Fdn, Biomed 2U, FI-00290 Helsinki, Finland..
    Kolcic, Ivana
    Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Kolovou, Genovefa
    Onassis Cardiac Surg Ctr, Dept Cardiol, Athens, Greece..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Kramer, Bernhard K.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Kvaloy, Kirsti
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, HUNT Res Ctr, N-7600 Levanger, Norway..
    Lakka, Timo A.
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Launer, Lenore J.
    Natl Inst Aging, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Lee, Nanette R.
    Univ San Carlos, Off Populat Studies Fdn Inc, Cebu 6000, Philippines.;Univ San Carlos, Dept Anthropol Sociol & Hist, Cebu 6000, Philippines..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England. Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Linneberg, Allan
    Minerva Fdn, Biomed 2U, FI-00290 Helsinki, Finland.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Lobbens, Stephane
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Loh, Marie
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;ASTAR, Agcy Sci Technol & Res, Translat Lab Genet Med TLGM, 8A Biomed Grove,Immunos Level 5, Singapore 138648, Singapore..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Luben, Robert
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Lubke, Gitta
    Univ Notre Dame, Dept Psychol, Notre Dame, IN 46556 USA..
    Ludolph-Donislawski, Anja
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Lupoli, Sara
    Univ Milan, Dept Hlth Sci, Via A Di Rudini 8, I-20142 Milan, Italy..
    Madden, Pamela A. F.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Mannikko, Reija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Marques-Vidal, Pedro
    Lausanne Univ Hosp CHUV, Dept Med Internal Med, Lausanne, Switzerland..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    McKenzie, Colin A.
    Univ West Indies, Trop Med Res Inst, Trop Metab Res Unit, Mona JMAAW15, Jamaica, NY USA..
    McKnight, Barbara
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Fred Hutchinson Canc Res Ctr, Program Biostat & Biomath, Seattle, WA 98109 USA..
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Menni, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Mol Epidemiol, Brisbane, Qld 4029, Australia..
    Musk, A. W. (Bill)
    Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Populat Hlth, 35 Stirling Hwy, Crawley, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia..
    Narisu, Narisu
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem, Greifswald, Germany.;Univ Med Greifswald, Lab Med, Greifswald, Germany..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Olden, Matthias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Ong, Ken K.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Padmanabhan, Sandosh
    Univ Aberdeen, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland.;Univ Glasgow, BHF Glasgow CardiovascRes Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Peyser, Patricia A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Pisinger, Charlotta
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth Sci, Dept Publ Hlth, Copenhagen, Denmark..
    Porteous, David J.
    Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland..
    Rankinen, Tuomo
    Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Rao, D. C.
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA..
    Rasmussen-Torvik, Laura J.
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA..
    Rawal, Rajesh
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Rice, Treva
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Bien, Stephanie A.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Sanna, Serena
    Cittadella Univ Monserrato, CNR, IRGB, I-09042 Monserrato, Italy..
    Sarzynski, Mark A.
    Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Sattar, Naveed
    BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow, Lanark, Scotland..
    Savonen, Kai
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Schlessinger, David
    Natl Inst Aging, NIH, Lab Genet, Baltimore, MD USA..
    Scholtens, Salome
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Schurmann, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA..
    Scott, Robert A.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    Siemelink, Marten A.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    Silbernagel, Gunther
    Med Univ Graz, Dept Internal Med, Div Angiol, Graz, Austria..
    Slagboom, P. Eline
    Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Staessen, Jan A.
    Univ Leuven, Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Campus Sint Rafael,Kapucijnenvoer 35, Leuven, Belgium.;Maastricht Univ, R&D VitaK Grp, Brains Unlimited Bldg,Oxfordlaan 55, Maastricht, Netherlands..
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Fac Med, Glasgow, Lanark, Scotland..
    Swertz, Morris A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Swift, Amy J.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Taylor, Kent D.
    Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst Harbor, Ctr Translat Genom & Populat Sci, Torrance, CA USA.;Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA USA..
    Tayo, Bamidele O.
    Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA..
    Thorand, Barbara
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Thuillier, Dorothee
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Tuomilehto, Jaakko
    Dasman Diabet Inst, Res Div, Kuwait, Kuwait.;Danube Univ Krems, Dept Neurosci & Prevent Med, Krems 3500, Austria. Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland.;King Abdulaziz Univ, Saudi Diabet Res Grp, Jeddah, Saudi Arabia..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods, Quebec City G1V 0A6, PQ, Canada.;Univ Laval, Sch Nutr, Laval, PQ, Canada..
    Volzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Vonk, Judith M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Waeber, Gerard
    Lausanne Univ Hosp CHUV, Dept Med Internal Med, Lausanne, Switzerland..
    Waldenberger, Melanie
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Westendorp, R. G. J.
    Univ Copenhagen, Dept Publ Hlth, DK-1014 Copenhagen, Denmark.;Univ Copenhagen, Ctr Healthy Aging, DK-1014 Copenhagen, Denmark..
    Wild, Sarah
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Willemsen, Gonneke
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands..
    Wolffenbuttel, Bruce H. R.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Wright, Alan F.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Zhao, Wei
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Balkau, Beverley
    INSERM, U 1018, F-94807 Villejuif, France..
    Bandinelli, Stefania
    Azienda USL Toscana Ctr, Geriatr Unit, Florence, Italy..
    Boger, Carsten A.
    Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Boomsma, Dorret I.
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands..
    Bouchard, Claude
    Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Bruinenberg, Marcel
    Lifelines Cohort Study, POB 30001, NL-9700 RB Groningen, Netherlands..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA..
    Chen, Yii-Der Ida
    Univ Calif Los Angeles, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Univ Calif Los Angeles, Dept Pediat Harbor, Torrance, CA 90502 USA..
    Chines, Peter S.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Cooper, Richard S.
    Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA..
    Cucca, Francesco
    Cittadella Univ Monserrato, CNR, IRGB, I-09042 Monserrato, Italy.;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy..
    Cusi, Daniele
    Sanipedia Srl, Bresso, Milano, Italy.;Inst Biomed Technol Natl Ctr Res Segrate, Milan, Italy..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Ferrucci, Luigi
    Natl Inst Aging, Translat Gerontol Branch, Baltimore, MD USA..
    Franks, Paul W.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Froguel, Philippe
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France.;Imperial Coll London, Dept Genom Common Dis, London, England..
    Gordon-Larsen, Penny
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27516 USA..
    Grabe, Hans-Jorgen
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany.;German Ctr Neurodegenerat Dis DZNE, Rostock & Greifswald Site, Greifswald, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Haiman, Christopher A.
    Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, HUNT Res Ctr, N-7600 Levanger, Norway..
    Johnson, Andrew D.
    Framingham Heart Dis Epidemiol Study, NIH, Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA..
    Jukema, Wouter
    Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Kardia, Sharon L. R.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Hammersmith Hosp, Fac Med, Natl Heart & Lung Inst, Hammersmith Campus, London, England..
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere 33014, Finland..
    Le Marchand, Loic
    Univ Hawaii, Canc Ctr, Epidemiol Program, Honolulu, HI 96813 USA..
    Marz, Winfried
    Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.;Med Univ Graz, Clin Inst Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res NIHR, Oxford, England..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Palmer, Lyle J.
    Univ Adelaide, Sch Publ Hlth, Adelaide, SA 5005, Australia..
    Pasterkamp, Gerard
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands.;UMC Utrecht, Div Labs & Pharm, Lab Clin Chem & Hematol, Utrecht, Netherlands..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Peters, Annette
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Polasek, Ozren
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.;Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Qi, Lu
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Smith, Blair H.
    Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland. Univ Dundee, Ninewells Hosp, Div Populat Hlth Sci, Dundee DD2 4RB, Scotland. Univ Dundee, Med Sch, Dundee DD2 4RB, Scotland..
    Sorensen, Thorkild I. A.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Bispebjerg & Frederiksberg Hosp, Dept Clin Epidemiol, Copenhagen, Denmark.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Tiemeier, Henning
    Erasmus MC, Dept Psychiat, Rotterdam, Netherlands..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Van der Harst, Pim
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands..
    Vestergaard, Henrik
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Steno Diabet Ctr, Gentofte, Denmark..
    Vollenweider, Peter
    Lausanne Univ Hosp CHUV, Dept Med Internal Med, Lausanne, Switzerland..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Weir, David R.
    Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48109 USA..
    Whitfield, John B.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    Wilson, James F.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Tyrrell, Jessica
    Univ Exeter, Med Sch, Genet Complex Traits, RILD Bldg, Exeter EX2 5DW, Devon, England.;Univ Exeter, European Ctr Environm & Human Hlth, Med Sch, Truro TR1 3HD, England..
    Frayling, Timothy M.
    Univ Exeter, Med Sch, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Cambridge, England.;Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Box 289,Level 4, Cambridge CB2 OQQ, England.;Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Level 4,Box 289, Cambridge CB2 OQQ, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Deloukas, Panagiotis
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Wellcome Trust Sanger Inst, Cambridge, England.;King Abdulaziz Univ, PACER HD, Jeddah, Saudi Arabia..
    Fox, Caroline S.
    NHLBI Framingham Heart Study, Framingham, MA 01702 USA..
    Hirschhorn, Joel N.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Genet, Boston, MA 02115 USA..
    Hunter, David J.
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA.;Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Strachan, David P.
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.;St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England..
    van Duijn, Cornelia M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands.;Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, Leiden, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    Heid, Iris M.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Marchini, Jonathan
    Univ Oxford, Dept Stat, Oxford, England..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA.;Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.;Mt Sinai Sch Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Kilpelainen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    North, Kari E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;NHLBI Framingham Heart Study, Framingham, MA 01702 USA..
    Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits2017Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 14977Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

  • 115.
    Kamble, Prasad G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Lundkvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Cook, Naomi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Franks, Paul W.
    Lund Univ, Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers2017Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 4, s. 234-242Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIM: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype-phenotype relationships.

    METHODS: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments.

    RESULTS: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups.

    CONCLUSIONS: Our report highlights that from a practical perspective, GBR can be used to study genotype-phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

  • 116.
    Kamble, Prasad G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lundkvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Castillejo-Lopez, Casimiro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA..
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    PPARG Pro12Ala variant in relation to adipose tissue metabolism and differentiation: a small genotype-based recall study2017Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr S1, s. S173-S173, artikkel-id 375Artikkel i tidsskrift (Annet vitenskapelig)
  • 117.
    Kamble, Prasad G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Gustafsson, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lundkvist, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Castillejo-Lopez, Casimiro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover.2018Inngår i: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 7, nr 4, s. 285-296Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target genes expression were investigated and compared between the genotype groups. On fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p<0.05) also accompanied with a higher antilipolytic effect of insulin post-OGTT (p<0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.

  • 118. Kaptoge, Stephen
    et al.
    Di Angelantonio, Emanuele
    Pennells, Lisa
    Wood, Angela M
    White, Ian R
    Gao, Pei
    Walker, Matthew
    Thompson, Alexander
    Sarwar, Nadeem
    Caslake, Muriel
    Butterworth, Adam S
    Amouyel, Philippe
    Assmann, Gerd
    Bakker, Stephan J L
    Barr, Elizabeth L M
    Barrett-Connor, Elizabeth
    Benjamin, Emelia J
    Björkelund, Cecilia
    Brenner, Hermann
    Brunner, Eric
    Clarke, Robert
    Cooper, Jackie A
    Cremer, Peter
    Cushman, Mary
    Dagenais, Gilles R
    D'Agostino, Ralph B
    Dankner, Rachel
    Davey-Smith, George
    Deeg, Dorly
    Dekker, Jacqueline M
    Engström, Gunnar
    Folsom, Aaron R
    Fowkes, F Gerry R
    Gallacher, John
    Gaziano, J Michael
    Giampaoli, Simona
    Gillum, Richard F
    Hofman, Albert
    Howard, Barbara V
    Ingelsson, Erik
    Iso, Hiroyasu
    Jørgensen, Torben
    Kiechl, Stefan
    Kitamura, Akihiko
    Kiyohara, Yutaka
    Koenig, Wolfgang
    Kromhout, Daan
    Kuller, Lewis H
    Lawlor, Debbie A
    Meade, Tom W
    Nissinen, Aulikki
    Nordestgaard, Børge G
    Onat, Altan
    Panagiotakos, Demosthenes B
    Psaty, Bruce M
    Rodriguez, Beatriz
    Rosengren, Annika
    Salomaa, Veikko
    Kauhanen, Jussi
    Salonen, Jukka T
    Shaffer, Jonathan A
    Shea, Steven
    Ford, Ian
    Stehouwer, Coen D A
    Strandberg, Timo E
    Tipping, Robert W
    Tosetto, Alberto
    Wassertheil-Smoller, Sylvia
    Wennberg, Patrik
    Westendorp, Rudi G
    Whincup, Peter H
    Wilhelmsen, Lars
    Woodward, Mark
    Lowe, Gordon D O
    Wareham, Nicholas J
    Khaw, Kay-Tee
    Sattar, Naveed
    Packard, Chris J
    Gudnason, Vilmundur
    Ridker, Paul M
    Pepys, Mark B
    Thompson, Simon G
    Danesh, John
    C-reactive protein, fibrinogen, and cardiovascular disease prediction2012Inngår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, nr 14, s. 1310-1320Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events.

    METHODS:

    We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen.

    RESULTS:

    The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years.

    CONCLUSIONS:

    In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).

  • 119. Kasiman, Katherine
    et al.
    Lundholm, Cecilia
    Sandin, Sven
    Malki, Ninoa
    Sparen, Pär
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Common Familial Effects on Ischemic Stroke and Myocardial Infarction: A Prospective Population-Based Cohort Study2014Inngår i: Frontiers in Cardiovascular Medicine, ISSN 1539-4565, E-ISSN 2296-701X, s. 1-10-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Recent genome-wide association studies suggest some overlap of genetic determinants of ischemic stroke (IS) and myocardial infarction (MI). This study aimed to assess shared familial risk between IS and MI in a large, population-wide cohort study.

    METHODS:

    Study participants free of IS and MI and their affected siblings were extracted from the Swedish Hospital Discharge and Cause of Death Registers between 1987 and 2007, forming an exposed sib-pair. They were matched by birth year of both siblings and calendar period to up to five unexposed sib-pairs. Stratified Cox regression analyses were used to assess familial risk of MI and IS in those exposed to having a sibling with IS (n = 31,659) and MI (n = 62,766), respectively, compared to unexposed (n = 143,728 and 265,974).

    RESULTS:

    The overall risk of MI when exposed to having a sibling with IS was statistically significantly increased (RR, 1.44; 95% CI, 1.34-1.55, p < 0.001) to a similar extent as risk of IS when exposed to having a sibling with MI (RR, 1.41; 95% CI, 1.32-1.50, p < 0.001). The familial risks were similar in full siblings for both groups (RR for MI, 1.46; 95% CI, 1.35-1.58, p < 0.001; and RR for IS, 1.40; 95% CI, 1.30-1.40, p < 0.001) and half siblings (RR for MI, 1.29; 95% CI, 1.05-1.59, p < 0.001; and RR for IS, 1.38; 95% CI, 1.16-1.65, p < 0.001).

    CONCLUSION:

    This large, population-wide study indicates that there is considerable overlap of familial risk between IS and MI.

  • 120. Kasiman, Katherine
    et al.
    Lundholm, Cecilia
    Sandin, Sven
    Malki, Ninoa
    Sparén, Pär
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Familial effects on ischemic stroke: the role of sibling kinship, sex, and age of onset2012Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 5, nr 2, s. 226-233Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Previous studies on familial risk of ischemic stroke have supported genetic influence on the disease incidence. This study aimed to characterize these familial effects in a nationwide population-based study by taking into account sibling relations, sex of siblings, and age of onset, with respect to ischemic stroke incidence.

    METHODS AND RESULTS: Incident ischemic stroke cases identified from the Swedish Hospital Discharge and Cause of Death Registers between 1987 and 2007 were linked to their stroke-free siblings (study participants), forming an exposed sib-pair. Each exposed sib-pair was matched up to 5 unexposed sib-pairs from the Multi-Generation Registry by birth and calendar years. Incident ischemic stroke risk was assessed using hazard estimates obtained from stratified Cox regression analyses. A total of 30 735 exposed and 152 391 unexposed study participants were included in the analyses. The overall risk of incident ischemic stroke when exposed was significantly increased (relative risk, 1.61; 95% confidence interval, 1.48-1.75; P<0.001). Familial risk was higher in full (relative risk, 1.64; 95% confidence interval, 1.50-1.81; P<0.001) than in half (relative risk, 1.41; 95% confidence interval, 1.10-1.82; P=0.007) siblings. Familial risk of early ischemic stroke almost doubled when exposed to early ischemic stroke (relative risk, 1.94; 95% confidence interval, 1.41-2.67; P<0.001).

    CONCLUSIONS: There was a 60% increased risk for ischemic stroke in individuals having a sibling with prior stroke. The familial effect was even higher for full-sibling relations. Familial effects were observed in both male and female individuals, and no differential effects depending on the sex of either of the siblings were found.

  • 121. Kilpeläinen, Tuomas O
    et al.
    Carli, Jayne F Martin
    Skowronski, Alicja A
    Sun, Qi
    Kriebel, Jennifer
    Feitosa, Mary F
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Drong, Alexander W
    Hayes, James E
    Zhao, Jinghua
    Pers, Tune H
    Schick, Ursula
    Grarup, Niels
    Kutalik, Zoltán
    Trompet, Stella
    Mangino, Massimo
    Kristiansson, Kati
    Beekman, Marian
    Lyytikäinen, Leo-Pekka
    Eriksson, Joel
    Henneman, Peter
    Lahti, Jari
    Tanaka, Toshiko
    Luan, Jian'an
    Greco M, Fabiola Del
    Pasko, Dorota
    Renström, Frida
    Willems, Sara M
    Mahajan, Anubha
    Rose, Lynda M
    Guo, Xiuqing
    Liu, Yongmei
    Kleber, Marcus E
    Pérusse, Louis
    Gaunt, Tom
    Ahluwalia, Tarunveer S
    Ju Sung, Yun
    Ramos, Yolande F
    Amin, Najaf
    Amuzu, Antoinette
    Barroso, Inês
    Bellis, Claire
    Blangero, John
    Buckley, Brendan M
    Böhringer, Stefan
    I Chen, Yii-Der
    de Craen, Anton J N
    Crosslin, David R
    Dale, Caroline E
    Dastani, Zari
    Day, Felix R
    Deelen, Joris
    Delgado, Graciela E
    Demirkan, Ayse
    Finucane, Francis M
    Ford, Ian
    Garcia, Melissa E
    Gieger, Christian
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hallmans, Göran
    Hankinson, Susan E
    Havulinna, Aki S
    Herder, Christian
    Hernandez, Dena
    Hicks, Andrew A
    Hunter, David J
    Illig, Thomas
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ioan-Facsinay, Andreea
    Jansson, John-Olov
    Jenny, Nancy S
    Jørgensen, Marit E
    Jørgensen, Torben
    Karlsson, Magnus
    Koenig, Wolfgang
    Kraft, Peter
    Kwekkeboom, Joanneke
    Laatikainen, Tiina
    Ladwig, Karl-Heinz
    LeDuc, Charles A
    Lowe, Gordon
    Lu, Yingchang
    Marques-Vidal, Pedro
    Meisinger, Christa
    Menni, Cristina
    Morris, Andrew P
    Myers, Richard H
    Männistö, Satu
    Nalls, Mike A
    Paternoster, Lavinia
    Peters, Annette
    Pradhan, Aruna D
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J
    Rathmann, Wolfgang
    Rice, Treva K
    Brent Richards, J
    Ridker, Paul M
    Sattar, Naveed
    Savage, David B
    Söderberg, Stefan
    Timpson, Nicholas J
    Vandenput, Liesbeth
    van Heemst, Diana
    Uh, Hae-Won
    Vohl, Marie-Claude
    Walker, Mark
    Wichmann, Heinz-Erich
    Widén, Elisabeth
    Wood, Andrew R
    Yao, Jie
    Zeller, Tanja
    Zhang, Yiying
    Meulenbelt, Ingrid
    Kloppenburg, Margreet
    Astrup, Arne
    Sørensen, Thorkild I A
    Sarzynski, Mark A
    Rao, D C
    Jousilahti, Pekka
    Vartiainen, Erkki
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, André G
    Kajantie, Eero
    Osmond, Clive
    Palotie, Aarno
    Eriksson, Johan G
    Heliövaara, Markku
    Knekt, Paul B
    Koskinen, Seppo
    Jula, Antti
    Perola, Markus
    Huupponen, Risto K
    Viikari, Jorma S
    Kähönen, Mika
    Lehtimäki, Terho
    Raitakari, Olli T
    Mellström, Dan
    Lorentzon, Mattias
    Casas, Juan P
    Bandinelli, Stefanie
    März, Winfried
    Isaacs, Aaron
    van Dijk, Ko W
    van Duijn, Cornelia M
    Harris, Tamara B
    Bouchard, Claude
    Allison, Matthew A
    Chasman, Daniel I
    Ohlsson, Claes
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Scott, Robert A
    Langenberg, Claudia
    Wareham, Nicholas J
    Ferrucci, Luigi
    Frayling, Timothy M
    Pramstaller, Peter P
    Borecki, Ingrid B
    Waterworth, Dawn M
    Bergmann, Sven
    Waeber, Gérard
    Vollenweider, Peter
    Vestergaard, Henrik
    Hansen, Torben
    Pedersen, Oluf
    Hu, Frank B
    Eline Slagboom, P
    Grallert, Harald
    Spector, Tim D
    Jukema, J W
    Klein, Robert J
    Schadt, Erik E
    Franks, Paul W
    Lindgren, Cecilia M
    Leibel, Rudolph L
    Loos, Ruth J F
    Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikkel-id 10494Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  • 122. Knowles, Joshua W.
    et al.
    Hao, Ke
    Xie, Weija
    Weedon, Michael N.
    Zhang, Zhongyang
    Paaanen, Jussil
    Goodarzi, Mark O.
    Hansson, Ola
    Pankow, James S.
    Chenemsetty, Indumathi
    Carcamo-Orive, Ivan
    Assimes, Themisrocles
    Morris, Andrew
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Chen, Yii-Der I.
    Schadt, Eric E.
    Makinen, Ville-Petteri
    Yang, Xia
    Abbasi, Fahi
    Attie, Alan
    Keller, Mark
    Greenawalt, Danielle
    Rotter, Jerome I.
    Sinako, Alan
    Hsiung, Agnes
    Cordell, Heather J.
    Reaven, Gerald
    Groop, Leif
    Laakso, Markku
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Frayling, Timothy M.
    Walker, Mark
    Quertermous, Thomas
    Genetic and Functional Analyses Identify NAT2 as a Human Insulin Sensitivity Gene2013Inngår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, nr 22Artikkel i tidsskrift (Annet vitenskapelig)
  • 123. Knowles, Joshua W.
    et al.
    Xie, Weijia
    Zhang, Zhongyang
    Chennemsetty, Indumathi
    Assimes, Themistocles L.
    Paananen, Jussi
    Hansson, Ola
    Pankow, James
    Goodarzi, Mark O.
    Carcamo-Orive, Ivan
    Morris, Andrew P.
    Chen, Yii-Der I.
    Maekinen, Ville-Petteri
    Ganna, Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mahajan, Anubha
    Guo, Xiuqing
    Abbasi, Fahim
    Greenawalt, Danielle M.
    Lum, Pek
    Molony, Cliona
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia
    Raffel, Leslie J.
    Tsao, Philip S.
    Schadt, Eric E.
    Rotter, Jerome I.
    Sinaiko, Alan
    Reaven, Gerald
    Yang, Xia
    Hsiung, Chao A.
    Groop, Leif
    Cordell, Heather J.
    Laakso, Markku
    Hao, Ke
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frayling, Timothy M.
    Weedon, Michael N.
    Walker, Mark
    Quertermous, Thomas
    Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene2015Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, nr 4, s. 1739-1751Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

  • 124.
    Kraja, Aldi T.
    et al.
    Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    Cook, James P.
    Univ Liverpool, Dept Biostatist, Liverpool, Merseyside, England..
    Warren, Helen R.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Surendran, Praveen
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA..
    Evangelou, Evangelos
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, Ioannina, Greece..
    Manning, Alisa K.
    Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.;Hebrew SeniorLife, Dept Med, Boston, MA USA..
    Grarup, Niels
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Drenos, Fotios
    Univ Bristol, Sch Social & Community Med, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England.;UCL, Ctr Cardiovasc Genet, Inst Cardiovasc Sci, London, England..
    Sim, Xueling
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Smith, Albert Vernon
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Blakemore, Alexandra I. F.
    Imperial Coll London, Sect Invest Med, Dept Med, London, England.;Brunel Univ, Dept Life Sci, London, England..
    Bork-Jensen, Jette
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Brandslund, Ivan
    Lillebaelt Hosp, Dept Clin Biochem, Vejle, Denmark.;Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark..
    Farmaki, Aliki-Eleni
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Fava, Cristiano
    Lund Univ, Dept Clin Sci, Malmo, Sweden.;Univ Verona, Dept Med, Verona, Italy..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Herzig, Karl-Heinz
    Univ Oulu, Res Unit Biomed, Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Med Res Ctr, Oulu, Finland.;Oulu Univ Hosp, Oulu, Finland.;Poznan Univ Med Sci, Dept Gastroenterol & Metab, Poznan, Poland..
    Giri, Ayush
    Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Nashville, TN 37235 USA..
    Giulianini, Franco
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Grove, Megan L.
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA..
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    Have, Christian T.
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Havulinna, Aki S.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Inst Mol Med Finland, Helsinki, Finland..
    Zhang, He
    Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Karajamaki, AnneMari
    Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland.;Vaasa Hlth Care Ctr, Diabet Ctr, Vaasa, Finland..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA..
    Linneberg, Allan
    Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark..
    Little, Louis
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England..
    Liu, Yongmei
    Wake Forest Baptist Med Ctr, Epidemiol & Prevent Ctr Genom & Personalized Med, Med Ctr Blvd, Winston Salem, NC USA.;Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Ingram Canc Ctr,Vanderbilt Ep, Nashville, TN 37212 USA..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Malerba, Giovanni
    Univ Verona, Dept Neurosci Biomed & Movement, Sect Biol & Genet, Verona, Italy..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    Mei, Hao
    Univ Mississippi, Med Ctr, Dept Data Sci, Jackson, MS 39216 USA..
    Menni, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Morrison, Alanna C.
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA..
    Padmanabhan, Sandosh
    Univ Glasgow, British Heart Fdn, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci,Glasgow Cardiovasc Res Ct, Glasgow, Lanark, Scotland..
    Palmas, Walter
    Columbia Univ, Dept Med, Med Ctr, New York, NY USA..
    Poveda, Alaitz
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Rauramaa, Rainer
    Univ Eastern Finland, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Rayner, Nigel William
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.;Kuopio Univ Hosp, Kuopio, Finland..
    Riaz, Muhammad
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England..
    Rice, Ken
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Richard, Melissa A.
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;McGovern Med Sch, Brown Fdn Inst Mol Med, Houston, TX 77030 USA..
    Smith, Jennifer A.
    Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA..
    Southam, Lorraine
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Kuopio Univ Hosp, Kuopio, Finland..
    Stancakova, Alena
    Univ Eastern Finland, Kuopio, Finland..
    Stirrups, Kathleen E.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;MRC BHF Cardiovasc Epidemiol Ctr, Dept Haematol, Cambridge, England..
    Tragante, Vinicius
    Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands..
    Tuomi, Tiinamaija
    Helsinki Univ Cent Hosp, Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Endocrinol, Helsinki, Finland.;Umea Univ, Dept Biobank Res, Umea, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Tzoulald, Ioanna
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.;Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, Ioannina, Greece..
    Varga, Tibor V.
    Univ Eastern Finland, Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Weiss, Stefan
    Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Berlin, Germany..
    Yiorkas, Andrianos M.
    Imperial Coll London, Sect Invest Med, Dept Med, London, England.;Brunel Univ, Dept Life Sci, London, England..
    Young, Robin
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England..
    Zhang, Weihua
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;London North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England..
    Barnes, Michael R.
    Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Cabrera, Claudia P.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Gao, He
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boerwinkle, Eric
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Chambers, John C.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;London North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Connell, John M.
    Univ Dundee, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Christensen, Cramer K.
    Lillebaelt Hosp, Med Dept, Vejle, Denmark..
    de Boer, Rudolf A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Psychol, Edinburgh, Midlothian, Scotland..
    Dedoussis, George
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Deloukas, Panos
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Dominiczak, Anna F.
    Univ Glasgow, British Heart Fdn, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci,Glasgow Cardiovasc Res Ct, Glasgow, Lanark, Scotland..
    Dorr, Marcus
    Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.;Univ Med Greifswald, Dept Internal Med B Cardiol Intens Care Med Infec, Greifswald, Germany..
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bldg 10, Bethesda, MD 20892 USA.;Hebrew SeniorLife, Inst Aging Res, Boston, MA USA..
    Edwards, Todd L.
    Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Nashville, TN 37235 USA..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Fornage, Myriam
    McGovern Med Sch, Brown Fdn Inst Mol Med, Houston, TX 77030 USA..
    Franceschini, Nora
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Franks, Paul W.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gambaro, Giovanni
    Univ Cattolica Sacro Cuore, Dept Nephrol & Dialysis, Rome, Italy..
    Groop, Leif
    Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Hallmans, Goran
    Umea Univ, Dept Biobank Res, Umea, Sweden..
    Hansen, Torben
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Heikki, Oksa
    Tampere Univ Hosp, Tampere, Finland..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland.;Dasman Diabet Inst, Kuwait, Kuwait.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Danube Univ Krems, Dept Neurosci & Prevent Med, Krems An Der Donau, Austria..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.;Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland..
    Kardia, Sharon L. R.
    Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA..
    Karpe, Fredrik
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Kooner, Jaspal S.
    London North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Natl Heart & Lung Inst, Hammersmith Hosp Campus, London, England..
    Lakka, Timo A.
    Univ Eastern Finland, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Dept Clin Physiol & Nucl Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio, Finland..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Moris, Andrwe P.
    Univ Liverpool, Dept Biostatist, Liverpool, Merseyside, England..
    Palmer, Colin N. A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland. Univ Split, Fac Med, Split, Croatia..
    Pedersen, Oluf
    Polasek, Ozren
    Poulter, Neil R.
    Imperial Coll London, Int Ctr Circulatory Hlth, London, England..
    Province, Michael A.
    Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.;Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA. Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA..
    Ridker, Paul M.
    Hebrew SeniorLife, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. Univ Edinburgh, Alzheimer Scotland Res Ctr, Edinburgh, Midlothian, Scotland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Samani, Nilesh J.
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England..
    Sever, Peter J.
    Imperial Coll London, Int Ctr Circulatory Hlth, London, England..
    Skaaby, Tea
    Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Stafford, Jeanette M.
    Starr, John M.
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    van der Meer, Peter
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Vergnaud, Anne-Claire
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Willer, Cristen J.
    Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Witte, Daniel R.
    Aarhus Univ, Dept Publ Hlth, Aarhus, Denmark.;Danish Diabet Acad, Odense, Denmark..
    Zeggini, Eleftheria
    Kuopio Univ Hosp, Kuopio, Finland..
    Saleheen, Danish
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Butterworth, Adam S.
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Cambridge Ctr Excellence, British Heart Fdn, Dept Med, Cambridge, England..
    Danesh, John
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England.;Univ Cambridge, Cambridge Ctr Excellence, British Heart Fdn, Dept Med, Cambridge, England.;Kuopio Univ Hosp, Kuopio, Finland..
    Asselbergs, Folkert W.
    UCL, Fac Populat Hlth Sci, London, England.;Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands..
    Wain, Louise V.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Ehret, Georg B.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA.;Geneva Univ Hosp, Dept Med, Geneva, Switzerland..
    Chasman, Daniel I.
    Hebrew SeniorLife, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Caulfield, Mark J.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.;Imperial Coll London, Natl Inst Hlth Res Imperial Coll Healthcare NHS T, Biomed Res Unit, London, England..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA..
    Newton-Cheh, Christopher
    Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Munroe, Patricia B.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England..
    Howson, Joanna M. M.
    Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England.;MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England..
    New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals2017Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, nr 5, artikkel-id e001778Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

    Methods and Results - Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

    Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

  • 125. Kumar, Jitender
    et al.
    Broeckling, Corey D.
    Wiklund, Fredrik
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Prenni, Jessica E.
    Influence of Biological and Technical Covariates on Non-targeted Metabolite Profiling in a Large-scale Epidemiological Study2013Inngår i: Current Metabolomics, ISSN 2213-235X, Vol. 1, nr 3, s. 220-226-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-targeted metabolite profiling using ultra performance liquid chromatography-mass spectrometry (UPLCMS) was performed as part of a large-scale epidemiological study involving biobanked serum samples. The influence of both biological (age and body mass index) and technical (season of sample collection, fasting time, handling time, and storage time) covariates on the analysis was assessed. Statistical models including different sets of these covariates were compared and the results illustrate that variation in which covariates were included did not have an appreciable effect on the number or composition of biologically significant metabolite features associated with body mass index or age. Furthermore, when all covariates were included in the model, there was little overlap of metabolite features significantly associated with the different covariates. Thus, the results of this study illustrate that while some of the observed quantitative variance of metabolite features can be explained by biological and technical covariates, the use of non-targeted metabolite profiling of serum by UPLC-MS is valid for studies of biological outcomes in biobanked clinical samples from large-scale studies. - See more at: http://www.eurekaselect.com/115259/article#sthash.BOvtwWe7.dpuf

  • 126.
    Kumar, Jitender
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    No Evidence of a Causal Relationship between Plasma Homocysteine and Type 2 Diabetes: A Mendelian Randomization Study2015Inngår i: Frontiers in Cardiovascular Medicine, ISSN 1539-4565, E-ISSN 2296-701X, Vol. 2, artikkel-id 11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Several observational studies have shown an association between increased circulating homocysteine and risk of type 2 diabetes (T2D). We aimed to assess whether this relation is causal using genetic data from large populations of individuals of European descent.

    METHODS: We investigated the association between homocysteine concentrations and blood glucose, plasma insulin, T2D in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort (n = 1,016). A score of five previously published single nucleotide polymorphisms (SNPs) from genes involved in homocysteine metabolism were utilized as genetic instrument for homocysteine concentrations. The effect estimate of this genetic score with T2D was determined using results from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (including 34,840 cases and 114,981 controls). Further, the effects of the genetic score with fasting glucose and insulin were determined using results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (up to 38,238 non-diabetic participants).

    RESULTS: The genetic score provided a strong instrument for homocysteine concentrations (P = 2.7 × 10(-143), F = 650). In the PIVUS cohort, we found an association of homocysteine with fasting insulin [β = 0.056 (95% CI 0.021, 0.090), P = 0.001], but not with incident diabetes. We did not find any evidence of a causal effect of homocysteine on fasting glucose, fasting insulin, or T2D (P > 0.05 for all analyses) when using data from DIAGRAM or MAGIC studies.

    CONCLUSION: No evidence of a causal relationship of levels of plasma homocysteine with fasting glucose, fasting insulin, or T2D was observed.

  • 127. Kumar, Jitender
    et al.
    Karlsson, Robert
    Broeckling, Corey D.
    Hong, Mun-Gwan
    Prince, Jonathan A.
    Prenni, Jessica E.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wiklund, Fredrik
    Associations of Body Mass Index and Obesity-Related Genetic Variants with Serum Metabolites2014Inngår i: Current Metabolomics, ISSN 2213-235X, Vol. 2, nr 1, s. 27-36-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Body mass index (BMI) is one of the most important risk factors for different metabolic and cardiovascular disorders. Previously, both genetic and environmental agents associated with BMI have been described. The main focus of this exploratory study was to find the circulating metabolites associated with BMI utilizing an untargeted metabolomics approach. Additionally, significant metabolites identified were studied for their relation with BMIassociated single nucleotide polymorphisms (SNPs). Materials and Methods: A total of 971 individuals from the Cancer of the Prostate in Sweden study (discovery sample- 275 prostate cancers patients and 182 controls; replication sample- 514 prostate cancer patients) were utilized. Blood samples were collected and serum metabolic profiling was obtained using ultra-performance liquid chromatography followed by mass spectrometry. Genotyping data was available for 26 out of 32 SNPs (21 genotyped and 5 proxies) previously robustly associated with BMI in individuals of European descent. Weighted genetic risk score was generated using these SNPs and studied for its association with metabolites. Results: A total of 6138 and 5209 metabolite features were detected in discovery and replication samples, respectively. Out of 6138 metabolite features in discovery sample, 201 were found to be significantly associated with BMI (p<8.15*10-6) after multiple testing correction. These 201 features were further investigated in the replication samples and 16 were found to be significantly associated with BMI (p<2.49*10-4). Seven of these significant features were isotopes for four of the primary metabolites. Four metabolites were putatively identified: monoacylglyceride (18:1), diacylglyrcerol (32:1) and two phosphatidylcholines (34:0 and 36:0). Weighted genetic score of BMI-associated SNPs was not associated with these four metabolites. Conclusion: Four identifiable metabolites (monoacylglyceride, diacyclglyrcerol and two phosphatidylcholines) were found to be significantly associated with BMI in both discovery and replication samples. Common variants associated with BMI did not show association with these four metabolites. - See more at: http://www.eurekaselect.com/120422/article#sthash.PgqffHqv.dpuf

  • 128.
    Kumar, Jitender
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample of men and women2014Inngår i: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 134, nr SI, s. 251-256Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Persistent organic pollutants (POPs) are stable organic compounds generated through different industrial activities. Liver is involved in the metabolism of POPs, and hence exposure to POPs may interfere with liver function. Although a few studies have shown adverse effects of POPs on liver function, large-scale studies involving humans are lacking. We performed this large population-based cross-sectional study to assess the associations between different POPs and liver dysfunction biomarkers.

    METHODS: A total of 992 individuals (all aged 70 years, 50% males) were recruited as part of Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. The total toxic equivalency (TEQ) value was calculated for seven mono-ortho and two non-ortho substituted polychlorinated biphenyls (PCBs) and octachloro-p-dibenzodioxin (OCDD) to assess their toxicological effects. The association of TEQ values, summary measures of 16 PCBs (sum of PCBs) and three organochlorine pesticides (sum of OC pesticides) with liver dysfunction biomarkers (bilirubin; alkaline phosphatase, ALP; alanine aminotransferase, ALT; and gamma-glutamyltransferase, GGT) was analyzed utilizing linear regression analysis.

    RESULTS: The mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=0.71, P=0.008), while sum of OC pesticide concentrations was negatively associated with ALP (β=-0.02, P=0.002) after adjusting for various potential confounders. When analyzed individually, a number of different POPs were associated with ALP, ALT and bilirubin. No such association with GGT was observed.

    CONCLUSION: Various POPs including PCBs, OCDD and pesticides were associated with the liver dysfunction biomarkers bilirubin, ALT and ALP, suggesting adverse effects on liver function from these environmental pollutants.

  • 129.
    Kumar, Jitender
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Monica P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    van Bavel, Bert
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Influence of persistent organic pollutants on oxidative stress in population-based samples2014Inngår i: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 114, s. 303-309Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and BC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (beta = 0.94; P = 2.9 * 10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: beta = 0.01; P = 6.0 *10(-7); GSSG/GSH: beta = 0.002; P = 9.7 * 10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress.

  • 130.
    Kumar, Jitender
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Salihovic, Samira
    van Bavel, Bert
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Persistent Organic Pollutants and Inflammatory Markers in a Cross-Sectional Study of Elderly Swedish People: The PIVUS Cohort2014Inngår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, nr 9, s. 977-983Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Persistent organic pollutants (POPs) are compounds that are generated through various industrial activities and released in the surrounding environment. Different animal studies have shown effects of different POPs on various inflammatory markers. OBJECTIVE: Because very few studies have been conducted in humans, we assessed the associations between different POPs and inflammatory markers in a large population-based sample of elderly men and women (all 70 years of age) from Sweden. METHODS: This cross-sectional study investigated the concentrations of several polychlorinated biphenyls (PCBs), organochlorine pesticides, polychlorinated dibenzo-p-dioxin, and brominated diphenyl ether congeners and their association with a number of inflammatory markers [vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, C-reactive protein (CRP), total leucocyte count, tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and interleukin 6 (IL-6)] in 992 individuals. These individuals were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. We used a total toxic equivalency (TEQ) value that measures toxicological effects with the relative potencies of various POPs. RESULTS: Following adjustment for potential confounders, the TEQ value (driven mainly by PCB-126) was significantly associated with levels of ICAM-1 (p < 10(-5)). A similar trend was also observed between sum of PCBs and VCAM-1 (p < 0.001). No significant associations were observed between levels of POPs and other inflammatory markers. CONCLUSIONS: TEQ values were associated with levels of ICAM-1, to a lesser degree also with VCAM-1, but not with CRP and several other inflammatory markers. These findings suggest an activation of vascular adhesion molecules by POPs, and particularly by PCB-126.

  • 131.
    Kumar, Jitender
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    van Bavel, Bert
    Ekdahl, Kristina Nilsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Nilsson, Bo
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Influence of persistent organic pollutants on the complement system in a population-based human sample2014Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 71, s. 94-100Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Persistent organic pollutants (POPS) are toxic compounds generated through various industrial activities and have adverse effects on human health. Studies performed in cell cultures and animals have revealed that POPs can alter immune-system functioning. The complement system is part of innate immune system that helps to clear pathogens from the body. We performed a large-scale population-based study to find out associations between summary measures of different POPs and different complement system markers. Methods: In this cross-sectional study, 16 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, octachloro-p-dibenzodioxin, and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) were analyzed for their association with levels of protein complement 3 (C3), 3a (C3a), 4 (C4) and C3a/C3 ratio. A total of 992 individuals (all aged 70 years, 50% females) were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. Regression analysis adjusting for a variety of confounders was performed to study the associations of different POP exposures (total toxic equivalency value or TEQ and sum of 16 PCBs) with protein complements. Results: The TEQ values were found to be positively associated with C3a (beta = 0.07, 95% CI = 0.017-0.131, p = 0.01) and C3a/C3 ratio (beta = 0.07, 95% Cl = 0.015-0.126, p = 0.01) taking possible confounders into account. The association observed was mainly driven by PCB-126. Conclusion: In this study involving 992 elderly individuals from the general population, we showed that POPs, mainly PCB-126, were associated with levels of complement system markers indicating that the association of these toxic compounds with downstream disease could be mediated by activation of immune system.

  • 132.
    Lee, Sangin
    et al.
    Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA.
    Pawitan, Yudi
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lee, Youngjo
    Seoul Natl Univ, Dept Stat, San56-1 Shin Lim Dong, Seoul 151747, South Korea.
    Sparse estimation of gene-gene interactions in prediction models2017Inngår i: Statistical Methods in Medical Research, ISSN 0962-2802, E-ISSN 1477-0334, Vol. 26, nr 5, s. 2319-2332Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Current assessment of gene-gene interactions is typically based on separate parallel analysis, where each interaction term is tested separately, while less attention has been paid on simultaneous estimation of interaction terms in a prediction model. As the number of interaction terms grows fast, sparse estimation is desirable from statistical and interpretability reasons. There is a large literature on sparse estimation, but there is a natural hierarchy between the interaction and its corresponding main effects that requires special considerations. We describe random-effect models that impose sparse estimation of interactions under both strong and weak-hierarchy constraints. We develop an estimation procedure based on the hierarchical-likelihood argument and show that the modelling approach is equivalent to a penalty-based method, with the advantage of the models being more transparent and flexible. We compare the procedure with some standard methods in a simulation study and illustrate its application in an analysis of gene-gene interaction model to predict body-mass index.

  • 133. Ligthart, Symen
    et al.
    Vaez, Ahmad
    Võsa, Urmo
    Stathopoulou, Maria G
    de Vries, Paul S
    Prins, Bram P
    Van der Most, Peter J
    Tanaka, Toshiko
    Naderi, Elnaz
    Rose, Lynda M
    Wu, Ying
    Karlsson, Robert
    Barbalic, Maja
    Lin, Honghuang
    Pool, René
    Zhu, Gu
    Macé, Aurélien
    Sidore, Carlo
    Trompet, Stella
    Mangino, Massimo
    Sabater-Lleal, Maria
    Kemp, John P
    Abbasi, Ali
    Kacprowski, Tim
    Verweij, Niek
    Smith, Albert V
    Huang, Tao
    Marzi, Carola
    Feitosa, Mary F
    Lohman, Kurt K
    Kleber, Marcus E
    Milaneschi, Yuri
    Mueller, Christian
    Huq, Mahmudul
    Vlachopoulou, Efthymia
    Lyytikäinen, Leo-Pekka
    Oldmeadow, Christopher
    Deelen, Joris
    Perola, Markus
    Zhao, Jing Hua
    Feenstra, Bjarke
    Amini, Marzyeh
    Lahti, Jari
    Schraut, Katharina E
    Fornage, Myriam
    Suktitipat, Bhoom
    Chen, Wei-Min
    Li, Xiaohui
    Nutile, Teresa
    Malerba, Giovanni
    Luan, Jian'an
    Bak, Tom
    Schork, Nicholas
    Del Greco M, Fabiola
    Thiering, Elisabeth
    Mahajan, Anubha
    Marioni, Riccardo E
    Mihailov, Evelin
    Eriksson, Joel
    Ozel, Ayse Bilge
    Zhang, Weihua
    Nethander, Maria
    Cheng, Yu-Ching
    Aslibekyan, Stella
    Ang, Wei
    Gandin, Ilaria
    Yengo, Loïc
    Portas, Laura
    Kooperberg, Charles
    Hofer, Edith
    Rajan, Kumar B
    Schurmann, Claudia
    den Hollander, Wouter
    Ahluwalia, Tarunveer S
    Zhao, Jing
    Draisma, Harmen H M
    Ford, Ian
    Timpson, Nicholas
    Teumer, Alexander
    Huang, Hongyan
    Wahl, Simone
    Liu, YongMei
    Huang, Jie
    Uh, Hae-Won
    Geller, Frank
    Joshi, Peter K
    Yanek, Lisa R
    Trabetti, Elisabetta
    Lehne, Benjamin
    Vozzi, Diego
    Verbanck, Marie
    Biino, Ginevra
    Saba, Yasaman
    Meulenbelt, Ingrid
    O'Connell, Jeff R
    Laakso, Markku
    Giulianini, Franco
    Magnusson, Patrik K E
    Ballantyne, Christie M
    Hottenga, Jouke Jan
    Montgomery, Grant W
    Rivadineira, Fernando
    Rueedi, Rico
    Steri, Maristella
    Herzig, Karl-Heinz
    Stott, David J
    Menni, Cristina
    Frånberg, Mattias
    St Pourcain, Beate
    Felix, Stephan B
    Pers, Tune H
    Bakker, Stephan J L
    Kraft, Peter
    Peters, Annette
    Vaidya, Dhananjay
    Delgado, Graciela
    Smit, Johannes H
    Großmann, Vera
    Sinisalo, Juha
    Seppälä, Ilkka
    Williams, Stephen R
    Holliday, Elizabeth G
    Moed, Matthijs
    Langenberg, Claudia
    Räikkönen, Katri
    Ding, Jingzhong
    Campbell, Harry
    Sale, Michele M
    Chen, Yii-Der I
    James, Alan L
    Ruggiero, Daniela
    Soranzo, Nicole
    Hartman, Catharina A
    Smith, Erin N
    Berenson, Gerald S
    Fuchsberger, Christian
    Hernandez, Dena
    Tiesler, Carla M T
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Liewald, David
    Fischer, Krista
    Mellström, Dan
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Wang, Yunmei
    Scott, William R
    Lorentzon, Matthias
    Beilby, John
    Ryan, Kathleen A
    Pennell, Craig E
    Vuckovic, Dragana
    Balkau, Beverly
    Concas, Maria Pina
    Schmidt, Reinhold
    Mendes de Leon, Carlos F
    Bottinger, Erwin P
    Kloppenburg, Margreet
    Paternoster, Lavinia
    Boehnke, Michael
    Musk, A W
    Willemsen, Gonneke
    Evans, David M
    Madden, Pamela A F
    Kähönen, Mika
    Kutalik, Zoltán
    Zoledziewska, Magdalena
    Karhunen, Ville
    Kritchevsky, Stephen B
    Sattar, Naveed
    Lachance, Genevieve
    Clarke, Robert
    Harris, Tamara B
    Raitakari, Olli T
    Attia, John R
    van Heemst, Diana
    Kajantie, Eero
    Sorice, Rossella
    Gambaro, Giovanni
    Scott, Robert A
    Hicks, Andrew A
    Ferrucci, Luigi
    Standl, Marie
    Lindgren, Cecilia M
    Starr, John M
    Karlsson, Magnus
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Li, Jun Z
    Chambers, John C
    Mori, Trevor A
    de Geus, Eco J C N
    Heath, Andrew C
    Martin, Nicholas G
    Auvinen, Juha
    Buckley, Brendan M
    de Craen, Anton J M
    Waldenberger, Melanie
    Strauch, Konstantin
    Meitinger, Thomas
    Scott, Rodney J
    McEvoy, Mark
    Beekman, Marian
    Bombieri, Cristina
    Ridker, Paul M
    Mohlke, Karen L
    Pedersen, Nancy L
    Morrison, Alanna C
    Boomsma, Dorret I
    Whitfield, John B
    Strachan, David P
    Hofman, Albert
    Vollenweider, Peter
    Cucca, Francesco
    Jarvelin, Marjo-Riitta
    Jukema, J Wouter
    Spector, Tim D
    Hamsten, Anders
    Zeller, Tanja
    Uitterlinden, André G
    Nauck, Matthias
    Gudnason, Vilmundur
    Qi, Lu
    Grallert, Harald
    Borecki, Ingrid B
    Rotter, Jerome I
    März, Winfried
    Wild, Philipp S
    Lokki, Marja-Liisa
    Boyle, Michael
    Salomaa, Veikko
    Melbye, Mads
    Eriksson, Johan G
    Wilson, James F
    Penninx, Brenda W J H
    Becker, Diane M
    Worrall, Bradford B
    Gibson, Greg
    Krauss, Ronald M
    Ciullo, Marina
    Zaza, Gianluigi
    Wareham, Nicholas J
    Oldehinkel, Albertine J
    Palmer, Lyle J
    Murray, Sarah S
    Pramstaller, Peter P
    Bandinelli, Stefania
    Heinrich, Joachim
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA USA; Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA USA.
    Deary, Ian J
    Mägi, Reedik
    Vandenput, Liesbeth
    van der Harst, Pim
    Desch, Karl C
    Kooner, Jaspal S
    Ohlsson, Claes
    Hayward, Caroline
    Lehtimäki, Terho
    Shuldiner, Alan R
    Arnett, Donna K
    Beilin, Lawrence J
    Robino, Antonietta
    Froguel, Philippe
    Pirastu, Mario
    Jess, Tine
    Koenig, Wolfgang
    Loos, Ruth J F
    Evans, Denis A
    Schmidt, Helena
    Smith, George Davey
    Slagboom, P Eline
    Eiriksdottir, Gudny
    Morris, Andrew P
    Psaty, Bruce M
    Tracy, Russell P
    Nolte, Ilja M
    Boerwinkle, Eric
    Visvikis-Siest, Sophie
    Reiner, Alex P
    Gross, Myron
    Bis, Joshua C
    Franke, Lude
    Franco, Oscar H
    Benjamin, Emelia J
    Chasman, Daniel I
    Dupuis, Josée
    Snieder, Harold
    Dehghan, Abbas
    Alizadeh, Behrooz Z
    Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders2018Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, nr 5, s. 691-706, artikkel-id S0002-9297(18)30320-3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

  • 134.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Div Geriatr Med, Malmo, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Cardiometabolic Proteins Associated with Metabolic Syndrome2019Inngår i: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 17, nr 5, s. 272-279Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Although metabolic syndrome (MetS) was described in the late 80s, the molecular mechanisms underlying clustering of risk factors in certain individuals are not fully understood. The present study used targeted proteomics to establish cardiometabolic proteins related to all MetS components, thereby providing new hypotheses regarding pathways involved in the pathogenesis of MetS.

    Methods: In the EpiHealth study, 249 cardiometabolic proteins were measured by proximity extension assay (PEA) and related to the five MetS components [consensus-modified National Cholesterol Education Program (NCEP) criteria] in 2,444 participants aged 45-75 years (50% women).

    Results: Thirty-one proteins were associated with systolic blood pressure following adjustment for age and sex (P < 0.000040, taking multiple testing into account). The corresponding number of proteins significantly associated with fasting glucose, waist circumference, high-density lipoprotein cholesterol, and serum triglycerides were 58, 132, 127, and 148. Twenty-two proteins were significantly related to all 5 MetS components, and of those, 20 were with MetS as a binary outcome (n = 600, 24% of the sample) following adjustment for age, sex, fat mass, and lifestyle factors (alcohol intake, smoking, education, and exercise habits).

    Conclusion: Using targeted proteomics, we identified 20 proteins reflecting a range of pathways, such as immunomodulation at different levels; regulation of adipocyte differentiation; lipid, carbohydrate, and amino acid metabolism; or insulin-like growth factor signaling, to be strongly associated with MetS independently of fat mass and lifestyle factors. Whether some of these proteins are causally involved in the pathogenesis of clustering of multiple risk factors in the same individual remains to be investigated.

  • 135.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kumar, Jitender
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Teerlink, Tom
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation2013Inngår i: Vascular Medicine, ISSN 1358-863X, E-ISSN 1477-0377, Vol. 18, nr 4, s. 192-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives:

    Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. The breakdown of ADMA is mainly governed by the activity of dimethylarginine dimethylaminohydrolases (DDAHs). We investigated if genetic variation in the DDAH1 and DDAH2 genes were related to ADMA and l-arginine levels, as well as measures of endothelium-dependent vasodilation.

    Methods:

    In 1016 70-year-old participants of the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (50% women), we measured endothelium-dependent vasodilation (EDV) using the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma l-arginine and ADMA levels were measured by high-performance liquid chromatography and 55 single nucleotide polymorphisms (SNPs) in the DDAH1 and DDAH2 genes were genotyped.

    Results:

    Several of the genotypes in the DDAH1 gene were highly significantly related to ADMA levels (p = 10−7 at best), but not to the l-arginine levels. No relationships between the genotypes in the DDAH2 gene and ADMA or l-arginine levels were found. None of the DDAH1 genotypes being closely related to ADMA levels were significantly related to EDV or FMD. Neither were any of the DDAH2 genotypes closely related to any of the measurements of vasoreactivity.

    Conclusion:

    A close relationship was seen between SNPs in the DDAH1, but not DDAH2, gene and ADMA levels. However, variation in those genes was not related to measures of EDV in this elderly population.

  • 136.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ng, Esther
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Lindgren, Cecilia
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA.
    Salihovic, Samira
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Sweden.
    Mahajan, Anubha
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Lampa, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Morris, Andrew P
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based sample2017Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, s. 212-218Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.

    METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p,p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.

    RESULTS: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192ng/g lipid (p=1.5×10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p=2.2×10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p=6.2×10(-9)) located 7kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p=3.8×10(-35)), but mediated only 4% of the effect of the lead SNP on p,p'-DDE levels.

    CONCLUSION: Circulating levels of p,p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p,p'-DDE levels.

  • 137.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Penell, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Luttropp, Karin
    Nordfors, Louise
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    van Bavel, Bert
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population2013Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 59, s. 456-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.

  • 138.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Penell, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Salihovic, Samira
    van Bavel, Bert
    Lind, P Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample2014Inngår i: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 133, s. 135-140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.

  • 139.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    A Detailed Cardiovascular Characterization of Obesity Without the Metabolic Syndrome2011Inngår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 31, nr 8, s. e27-e34Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Although obesity without metabolic disturbances has been regarded as harmless, we have recently shown that obese subjects without the metabolic syndrome (MetS) has an increased risk of cardiovascular (CV) disorders and mortality during long-term follow-up. To investigate the basis for that increased risk, we studied the impact of obesity without MetS on multiple markers of subclinical CV disease.

    Methods and Results: At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors study. According to body mass index (BMI)/MetS status, they were categorized as normal weight (BMI = 30 kg/m(2)) without MetS (n = 102), and obese with MetS (n = 118). Several different measurements of endothelial reactivity, arterial compliance (plethysmography and ultrasound), carotid artery atherosclerosis, and echocardiography were performed, and 7 markers of coagulation/fibrinolysis were measured. Subjects with obesity without MetS showed impaired vasoreactivity, a more echolucent carotid artery wall, increased left ventricular mass and function together with impaired coagulation/fibrinolysis compared with normal-weight subjects without the MetS (P < 0.05 to 0.001). The majority of these disturbances were also seen in overweight subjects without the MetS.

    Conclusion: In contrast to some previous studies, our data do not support that obesity without MetS is a benign condition, because obesity without MetS was associated with impairments in multiple markers of subclinical CV disease. This was also the case for overweight subjects without the MetS.

  • 140.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Hedenstiernalaboratoriet.
    Lampa, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlov, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA.
    Longitudinal effects of aging on plasma proteins levels in older adults - associations with kidney function and hemoglobin levels2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 2, artikkel-id e0212060Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels. Material and methods In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured. Results Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships. Conclusion The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.

  • 141.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med, Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Proteomic profiling of endothelium-dependent vasodilation2019Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 37, nr 1, s. 216-222Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: As endothelial dysfunction is an early event in atherosclerosis formation, we investigated if proteins previously related to cardiovascular disease also were related to endothelial function using a novel targeted proteomics approach.

    Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 850970, all aged 70 years), endothelium-dependent vasodilation (EDV) in the forearm was assessed by intraarterial infusion of acetylcholine. Flow-mediated vasodilation (FMD) was investigated in the brachial artery by ultrasound. The same investigations were carried out in the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 375-461, all aged 50 years). After strict quality control, 84 cardiovascular-related proteins measured by the proximity extension assay were studied in relation to EDV and FMD in PIVUS (discovery sample) and POEM (validation sample).

    Results: Of the 15 proteins being significantly related to EDV in PIVUS (false discovery rate < 0.025), seven could be replicated in POEM at nominal significance and same effect direction when adjusted for sex and storage time. Of those, only cathepsin D remained significant following further adjustment for traditional cardiovascular risk factors (beta, -0.08; 95% confidence interval, -0.16, -0.01; P = 0.033; change in ln-transformed EDV per 1-SD increase in protein level). No protein was significantly related to FMD.

    Conclusion: Using a discovery/validation approach in two samples, our results indicate an inverse association between plasma cathepsin D levels and endothelial-dependent vasodilation.

  • 142.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindahl, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis2015Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 242, nr 1, s. 205-210Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and aims: We used a proteomics array to simultaneously measure multiple proteins that have been suggested to be associated with atherosclerosis and related them to plaque prevalence in carotid arteries in a human population-based study. Methods: In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS; n = 931, 50% women, all aged 70 years), the number of carotid arteries with plaques was recorded by ultrasound. Levels of 82 proteins were assessed in plasma by a proximity extension assay (Proseek Multiplex CVD, Olink Bioscience, Uppsala, Sweden) and related to carotid measures in a regression framework. Results: Following adjustment for multiple testing with Bonferroni correction, seven of the proteins were significantly related to the number of carotid arteries affected by plaques in sex-adjusted models (osteoprotegrin, T-cell immunoglobulin and mucin domain (TIM)-1, growth/differentiation factor 15 (GDF-15), matrix metalloprotease-12 (MMP-12), renin, tumor necrosis factor ligand superfamily member 14 (TNFSF14) and growth hormone). Of these, renin (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.13-1.49 per standard deviation increase), growth hormone (OR, 1.24; 95% CI, 1.08-1.43), osteoprotegerin (OR, 1.22; 95% CI, 1.05-1.43) and TNFSF14 (OR, 1.17; 95% CI, 1.01-1.35) were related to plaque prevalence independently of each other and traditional cardiovascular risk factors. Conclusion: A novel targeted proteomics approach using the proximity extension technique discovered several new associations of candidate proteins with carotid artery plaque prevalence in a large human sample.

  • 143. Liu, C
    et al.
    Marioni, R E
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pfeiffer, L
    Tsai, P-C
    Reynolds, L M
    Just, A C
    Duan, Q
    Boer, C G
    Tanaka, T
    Elks, C E
    Aslibekyan, S
    Brody, J A
    Kühnel, B
    Herder, C
    Almli, L M
    Zhi, D
    Wang, Y
    Huan, T
    Yao, C
    Mendelson, M M
    Joehanes, R
    Liang, L
    Love, S-A
    Guan, W
    Shah, S
    McRae, A F
    Kretschmer, A
    Prokisch, H
    Strauch, K
    Peters, A
    Visscher, P M
    Wray, N R
    Guo, X
    Wiggins, K L
    Smith, A K
    Binder, E B
    Ressler, K J
    Irvin, M R
    Absher, D M
    Hernandez, D
    Ferrucci, L
    Bandinelli, S
    Lohman, K
    Ding, J
    Trevisi, L
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stolk, L
    Uitterlinden, A G
    Yet, I
    Castillo-Fernandez, J E
    Spector, T D
    Schwartz, J D
    Vokonas, P
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Li, Y
    Fornage, M
    Arnett, D K
    Wareham, N J
    Sotoodehnia, N
    Ong, K K
    van Meurs, J B J
    Conneely, K N
    Baccarelli, A A
    Deary, I J
    Bell, J T
    North, K E
    Liu, Y
    Waldenberger, M
    London, S J
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Levy, D
    A DNA methylation biomarker of alcohol consumption.2018Inngår i: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, s. 422-433Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

  • 144. Locke, Adam E
    et al.
    Kahali, Bratati
    Berndt, Sonja I
    Justice, Anne E
    Pers, Tune H
    Day, Felix R
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L
    Yang, Jian
    Croteau-Chonka, Damien C
    Esko, Tonu
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ferreira, Teresa
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kutalik, Zoltán
    Luan, Jian'an
    Mägi, Reedik
    Randall, Joshua C
    Winkler, Thomas W
    Wood, Andrew R
    Workalemahu, Tsegaselassie
    Faul, Jessica D
    Smith, Jennifer A
    Hua Zhao, Jing
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karjalainen, Juha
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Medland, Sarah E
    Nalls, Michael A
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Shungin, Dmitry
    Stančáková, Alena
    Strawbridge, Rona J
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Attwood, Antony P
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Blagieva, Roza
    Blüher, Matthias
    Böhringer, Stefan
    Bonnycastle, Lori L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Caspersen, Ida H
    Ida Chen, Yii-Der
    Clarke, Robert
    Warwick Daw, E
    de Craen, Anton J M
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S F
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Goodall, Alison H
    Gordon, Scott D
    Gorski, Mathias
    Grabe, Hans-Jörgen
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    Groves, Christopher J
    Gusto, Gaëlle
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L
    Jeff, Janina M
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindström, Jaana
    Sin Lo, Ken
    Lobbens, Stéphane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Nagaraja, Ramaiah
    Nöthen, Markus M
    Nolte, Ilja M
    Pilz, Stefan
    Rayner, Nigel W
    Renstrom, Frida
    Rettig, Rainer
    Ried, Janina S
    Ripke, Stephan
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Scott, William R
    Seufferlein, Thomas
    Shi, Jianxin
    Vernon Smith, Albert
    Smolonska, Joanna
    Stanton, Alice V
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tan, Sian-Tsung
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Warren, Helen R
    Waterworth, Dawn
    Weedon, Michael N
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Brennan, Eoin P
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W
    Eriksson, Per
    Franco-Cereceda, Anders
    Gådin, Jesper R
    Gharavi, Ali G
    Goddard, Michael E
    Handsaker, Robert E
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McCarroll, Steven A
    McKnight, Amy J
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Okada, Yukinori
    Perry, John R B
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Scott, Robert A
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    Van't Hooft, Ferdinand M
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T
    Heath, Andrew C
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I
    Chines, Peter S
    Collins, Francis S
    Crawford, Dana C
    Adrienne Cupples, L
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Dominiczak, Anna F
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Felix, Stephan B
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Homuth, Georg
    Kees Hovingh, G
    Humphries, Steve E
    Hunt, Steven C
    Hyppönen, Elina
    Illig, Thomas
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jöckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Wouter Jukema, J
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Knekt, Paul
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lyssenko, Valeriya
    Männistö, Satu
    Marette, André
    Matise, Tara C
    McKenzie, Colin A
    McKnight, Barbara
    Moll, Frans L
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Madden, Pamela A F
    Pasterkamp, Gerard
    Peden, John F
    Peters, Annette
    Postma, Dirkje S
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Rioux, John D
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schunkert, Heribert
    Schwarz, Peter E H
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Trégouët, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Willemsen, Gonneke
    Witteman, Jacqueline C
    Zillikens, M Carola
    Adair, Linda S
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Metspalu, Andres
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E
    Saleheen, Danish
    Sattar, Naveed
    Schadt, Eric E
    Schlessinger, David
    Eline Slagboom, P
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Weir, David R
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Heid, Iris M
    O'Connell, Jeffrey R
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    Franke, Lude
    Frayling, Timothy M
    McCarthy, Mark I
    Visscher, Peter M
    Scherag, André
    Willer, Cristen J
    Boehnke, Michael
    Mohlke, Karen L
    Lindgren, Cecilia M
    Beckmann, Jacques S
    Barroso, Inês
    North, Kari E
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hirschhorn, Joel N
    Loos, Ruth J F
    Speliotes, Elizabeth K
    Genetic studies of body mass index yield new insights for obesity biology2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, nr 7538, s. 197-206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 145. Loth, Daan W
    et al.
    Artigas, María Soler
    Gharib, Sina A
    Wain, Louise V
    Franceschini, Nora
    Koch, Beate
    Pottinger, Tess D
    Smith, Albert Vernon
    Duan, Qing
    Oldmeadow, Chris
    Lee, Mi Kyeong
    Strachan, David P
    James, Alan L
    Huffman, Jennifer E
    Vitart, Veronique
    Ramasamy, Adaikalavan
    Wareham, Nicholas J
    Kaprio, Jaakko
    Wang, Xin-Qun
    Trochet, Holly
    Kähönen, Mika
    Flexeder, Claudia
    Albrecht, Eva
    Lopez, Lorna M
    de Jong, Kim
    Thyagarajan, Bharat
    Alves, Alexessander Couto
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Omenaas, Ernst
    Joshi, Peter K
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Viñuela, Ana
    Launer, Lenore J
    Loehr, Laura R
    Fornage, Myriam
    Li, Guo
    Wilk, Jemma B
    Tang, Wenbo
    Manichaikul, Ani
    Lahousse, Lies
    Harris, Tamara B
    North, Kari E
    Rudnicka, Alicja R
    Hui, Jennie
    Gu, Xiangjun
    Lumley, Thomas
    Wright, Alan F
    Hastie, Nicholas D
    Campbell, Susan
    Kumar, Rajesh
    Pin, Isabelle
    Scott, Robert A
    Pietiläinen, Kirsi H
    Surakka, Ida
    Liu, Yongmei
    Holliday, Elizabeth G
    Schulz, Holger
    Heinrich, Joachim
    Davies, Gail
    Vonk, Judith M
    Wojczynski, Mary
    Pouta, Anneli
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Wild, Sarah H
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rivadeneira, Fernando
    Völzke, Henry
    Hysi, Pirro G
    Eiriksdottir, Gudny
    Morrison, Alanna C
    Rotter, Jerome I
    Gao, Wei
    Postma, Dirkje S
    White, Wendy B
    Rich, Stephen S
    Hofman, Albert
    Aspelund, Thor
    Couper, David
    Smith, Lewis J
    Psaty, Bruce M
    Lohman, Kurt
    Burchard, Esteban G
    Uitterlinden, André G
    Garcia, Melissa
    Joubert, Bonnie R
    McArdle, Wendy L
    Musk, A Bill
    Hansel, Nadia
    Heckbert, Susan R
    Zgaga, Lina
    van Meurs, Joyce B J
    Navarro, Pau
    Rudan, Igor
    Oh, Yeon-Mok
    Redline, Susan
    Jarvis, Deborah L
    Zhao, Jing Hua
    Rantanen, Taina
    O'Connor, George T
    Ripatti, Samuli
    Scott, Rodney J
    Karrasch, Stefan
    Grallert, Harald
    Gaddis, Nathan C
    Starr, John M
    Wijmenga, Cisca
    Minster, Ryan L
    Lederer, David J
    Pekkanen, Juha
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Campbell, Harry
    Morris, Andrew P
    Gläser, Sven
    Hammond, Christopher J
    Burkart, Kristin M
    Beilby, John
    Kritchevsky, Stephen B
    Gudnason, Vilmundur
    Hancock, Dana B
    Williams, O Dale
    Polasek, Ozren
    Zemunik, Tatijana
    Kolcic, Ivana
    Petrini, Marcy F
    Wjst, Matthias
    Kim, Woo Jin
    Porteous, David J
    Scotland, Generation
    Smith, Blair H
    Viljanen, Anne
    Heliövaara, Markku
    Attia, John R
    Sayers, Ian
    Hampel, Regina
    Gieger, Christian
    Deary, Ian J
    Boezen, H Marike
    Newman, Anne
    Jarvelin, Marjo-Riitta
    Wilson, James F
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Stricker, Bruno H
    Teumer, Alexander
    Spector, Timothy D
    Melén, Erik
    Peters, Marjolein J
    Lange, Leslie A
    Barr, R Graham
    Bracke, Ken R
    Verhamme, Fien M
    Sung, Joohon
    Hiemstra, Pieter S
    Cassano, Patricia A
    Sood, Akshay
    Hayward, Caroline
    Dupuis, Josée
    Hall, Ian P
    Brusselle, Guy G
    Tobin, Martin D
    London, Stephanie J
    Genome-wide association analysis identifies six new loci associated with forced vital capacity2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, s. 669-677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

  • 146. Lu, Yingchang
    et al.
    Day, Felix R
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Buchkovich, Martin L
    Na, Jianbo
    Bataille, Veronique
    Cousminer, Diana L
    Dastani, Zari
    Drong, Alexander W
    Esko, Tõnu
    Evans, David M
    Falchi, Mario
    Feitosa, Mary F
    Ferreira, Teresa
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haring, Robin
    Hysi, Pirro G
    Iles, Mark M
    Justice, Anne E
    Kanoni, Stavroula
    Lagou, Vasiliki
    Li, Rui
    Li, Xin
    Locke, Adam
    Lu, Chen
    Mägi, Reedik
    Perry, John R B
    Pers, Tune H
    Qi, Qibin
    Sanna, Marianna
    Schmidt, Ellen M
    Scott, William R
    Shungin, Dmitry
    Teumer, Alexander
    Vinkhuyzen, Anna A E
    Walker, Ryan W
    Westra, Harm-Jan
    Zhang, Mingfeng
    Zhang, Weihua
    Zhao, Jing Hua
    Zhu, Zhihong
    Afzal, Uzma
    Ahluwalia, Tarunveer Singh
    Bakker, Stephan J L
    Bellis, Claire
    Bonnefond, Amélie
    Borodulin, Katja
    Buchman, Aron S
    Cederholm, Tommy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Choh, Audrey C
    Choi, Hyung Jin
    Curran, Joanne E
    de Groot, Lisette C P G M
    De Jager, Philip L
    Dhonukshe-Rutten, Rosalie A M
    Enneman, Anke W
    Eury, Elodie
    Evans, Daniel S
    Forsen, Tom
    Friedrich, Nele
    Fumeron, Frédéric
    Garcia, Melissa E
    Gärtner, Simone
    Han, Bok-Ghee
    Havulinna, Aki S
    Hayward, Caroline
    Hernandez, Dena
    Hillege, Hans
    Ittermann, Till
    Kent, Jack W
    Kolcic, Ivana
    Laatikainen, Tiina
    Lahti, Jari
    Mateo Leach, Irene
    Lee, Christine G
    Lee, Jong-Young
    Liu, Tian
    Liu, Youfang
    Lobbens, Stéphane
    Loh, Marie
    Lyytikäinen, Leo-Pekka
    Medina-Gomez, Carolina
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Nalls, Mike A
    Nielson, Carrie M
    Oozageer, Laticia
    Pascoe, Laura
    Paternoster, Lavinia
    Polašek, Ozren
    Ripatti, Samuli
    Sarzynski, Mark A
    Shin, Chan Soo
    Narančić, Nina Smolej
    Spira, Dominik
    Srikanth, Priya
    Steinhagen-Thiessen, Elisabeth
    Sung, Yun Ju
    Swart, Karin M A
    Taittonen, Leena
    Tanaka, Toshiko
    Tikkanen, Emmi
    van der Velde, Nathalie
    van Schoor, Natasja M
    Verweij, Niek
    Wright, Alan F
    Yu, Lei
    Zmuda, Joseph M
    Eklund, Niina
    Forrester, Terrence
    Grarup, Niels
    Jackson, Anne U
    Kristiansson, Kati
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Lichtner, Peter
    Luan, Jian'an
    Mahajan, Anubha
    Männistö, Satu
    Palmer, Cameron D
    Ried, Janina S
    Scott, Robert A
    Stancáková, Alena
    Wagner, Peter J
    Demirkan, Ayse
    Döring, Angela
    Gudnason, Vilmundur
    Kiel, Douglas P
    Kühnel, Brigitte
    Mangino, Massimo
    Mcknight, Barbara
    Menni, Cristina
    O'Connell, Jeffrey R
    Oostra, Ben A
    Shuldiner, Alan R
    Song, Kijoung
    Vandenput, Liesbeth
    van Duijn, Cornelia M
    Vollenweider, Peter
    White, Charles C
    Boehnke, Michael
    Boettcher, Yvonne
    Cooper, Richard S
    Forouhi, Nita G
    Gieger, Christian
    Grallert, Harald
    Hingorani, Aroon
    Jørgensen, Torben
    Jousilahti, Pekka
    Kivimaki, Mika
    Kumari, Meena
    Laakso, Markku
    Langenberg, Claudia
    Linneberg, Allan
    Luke, Amy
    Mckenzie, Colin A
    Palotie, Aarno
    Pedersen, Oluf
    Peters, Annette
    Strauch, Konstantin
    Tayo, Bamidele O
    Wareham, Nicholas J
    Bennett, David A
    Bertram, Lars
    Blangero, John
    Blüher, Matthias
    Bouchard, Claude
    Campbell, Harry
    Cho, Nam H
    Cummings, Steven R
    Czerwinski, Stefan A
    Demuth, Ilja
    Eckardt, Rahel
    Eriksson, Johan G
    Ferrucci, Luigi
    Franco, Oscar H
    Froguel, Philippe
    Gansevoort, Ron T
    Hansen, Torben
    Harris, Tamara B
    Hastie, Nicholas
    Heliövaara, Markku
    Hofman, Albert
    Jordan, Joanne M
    Jula, Antti
    Kähönen, Mika
    Kajantie, Eero
    Knekt, Paul B
    Koskinen, Seppo
    Kovacs, Peter
    Lehtimäki, Terho
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Liu, Yongmei
    Orwoll, Eric S
    Osmond, Clive
    Perola, Markus
    Pérusse, Louis
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Rivadeneira, Fernando
    Rudan, Igor
    Salomaa, Veikko
    Sørensen, Thorkild I A
    Stumvoll, Michael
    Tönjes, Anke
    Towne, Bradford
    Tranah, Gregory J
    Tremblay, Angelo
    Uitterlinden, André G
    van der Harst, Pim
    Vartiainen, Erkki
    Viikari, Jorma S
    Vitart, Veronique
    Vohl, Marie-Claude
    Völzke, Henry
    Walker, Mark
    Wallaschofski, Henri
    Wild, Sarah
    Wilson, James F
    Yengo, Loïc
    Bishop, D Timothy
    Borecki, Ingrid B
    Chambers, John C
    Cupples, L Adrienne
    Dehghan, Abbas
    Deloukas, Panos
    Fatemifar, Ghazaleh
    Fox, Caroline
    Furey, Terrence S
    Franke, Lude
    Han, Jiali
    Hunter, David J
    Karjalainen, Juha
    Karpe, Fredrik
    Kaplan, Robert C
    Kooner, Jaspal S
    McCarthy, Mark I
    Murabito, Joanne M
    Morris, Andrew P
    Bishop, Julia A N
    North, Kari E
    Ohlsson, Claes
    Ong, Ken K
    Prokopenko, Inga
    Richards, J Brent
    Schadt, Eric E
    Spector, Tim D
    Widén, Elisabeth
    Willer, Cristen J
    Yang, Jian
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Mohlke, Karen L
    Hirschhorn, Joel N
    Pospisilik, John Andrew
    Zillikens, M Carola
    Lindgren, Cecilia
    Kilpeläinen, Tuomas Oskari
    Loos, Ruth J F
    New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikkel-id 10495Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

  • 147.
    Lytsy, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Interplay of overweight and insulin resistance on hypertension development2014Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 32, nr 4, s. 834-839Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Obesity and hypertension are associated, possibly through causal pathways involving insulin resistance and metabolic derangements. We aimed to investigate in a whites sample if overweight or obese persons without insulin resistance are at risk of developing hypertension or blood pressure progression. Methods: In a meta-analysis, using multivariable-adjusted mixed-effects logistic regression models, we investigated the risks of hypertension development and blood pressure progression by combinations of relative weight classes and presence or absence of insulin resistance (defined as highest vs. lower three quartiles using the homeostatic model assessment method) in the Uppsala Longitudinal Study of Adult Men (n = 2322) and the Prospective Investigation of the Vasculature in Uppsala Seniors studies (n = 1066). These two samples, consisting mainly of middle-aged and elderly men, provided 1846 observations for the development of hypertension in normotensive individuals and 4223 observations for progressing to a higher blood pressure stage. Results: During a median of 10 years of follow-up, 884 (47.9%) developed hypertension and 1639 (38.8%) progressed to a higher blood pressure stage. Overweight or obese persons without insulin resistance had an increased risk of hypertension development [odds ratio (OR) 1.46, 95% confidence interval 1.14-1.88] and blood pressure progression (OR 1.32, 1.10-1.59) compared with normal-weight persons without insulin resistance. Conclusion: According to this study, being overweight or obese without insulin resistance increases the risk of hypertension and blood pressure progression. This adds to the evidence that overweight and obesity may be harmful per se, and that overweight and obesity without glucometabolic derangements are not benign conditions.

  • 148. Maddock, Jane
    et al.
    Zhou, Ang
    Cavadino, Alana
    Kuźma, Elżbieta
    Bao, Yanchun
    Smart, Melissa C
    Saum, Kai-Uwe
    Schöttker, Ben
    Engmann, Jorgen
    Kjærgaard, Marie
    Karhunen, Ville
    Zhan, Yiqiang
    Lehtimäki, Terho
    Rovio, Suvi P
    Byberg, Liisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Lahti, Jari
    Marques-Vidal, Pedro
    Sen, Abhijit
    Perna, Laura
    Schirmer, Henrik
    Singh-Manoux, Archana
    Auvinen, Juha
    Hutri-Kähönen, Nina
    Kähönen, Mika
    Kilander, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Räikkönen, Katri
    Melhus, Håkan
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Guessous, Idris
    Petrovic, Katja E
    Schmidt, Helena
    Schmidt, Reinhold
    Vollenweider, Peter
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Eriksson, Johan G
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Raitakari, Olli T
    Hägg, Sara
    Pedersen, Nancy L
    Herzig, Karl-Heinz
    Järvelin, Marjo-Riitta
    Veijola, Juha
    Kivimaki, Mika
    Jorde, Rolf
    Brenner, Hermann
    Kumari, Meena
    Power, Chris
    Llewellyn, David J
    Hyppönen, Elina
    Vitamin D and cognitive function: A Mendelian randomisation study.2017Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikkel-id 13230Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.

  • 149. Magnusson, Patrik K E
    et al.
    Almqvist, Catarina
    Rahman, Iffat
    Ganna, Andrea
    Viktorin, Alexander
    Walum, Hasse
    Halldner, Linda
    Lundström, Sebastian
    Ullén, Fredrik
    Långström, Niklas
    Larsson, Henrik
    Nyman, Anastasia
    Gumpert, Clara Hellner
    Råstam, Maria
    Anckarsäter, Henrik
    Cnattingius, Sven
    Johannesson, Magnus
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Klareskog, Lars
    de Faire, Ulf
    Pedersen, Nancy L
    Lichtenstein, Paul
    The Swedish Twin Registry: establishment of a biobank and other recent developments2013Inngår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 16, nr 1, s. 317-329Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Swedish Twin Registry (STR) today contains more than 194,000 twins and more than 75,000 pairs have zygosity determined by an intra-pair similarity algorithm, DNA, or by being of opposite sex. Of these, approximately 20,000, 25,000, and 30,000 pairs are monozygotic, same-sex dizygotic, and opposite-sex dizygotic pairs, respectively. Since its establishment in the late 1950s, the STR has been an important epidemiological resource for the study of genetic and environmental influences on a multitude of traits, behaviors, and diseases. Following large investments in the collection of biological specimens in the past 10 years we have now established a Swedish twin biobank with DNA from 45,000 twins and blood serum from 15,000 twins, which effectively has also transformed the registry into a powerful resource for molecular studies. We here describe the main projects within which the new collections of both biological samples as well as phenotypic measures have been collected. Coverage by year of birth, zygosity determination, ethnic heterogeneity, and influences of in vitro fertilization are also described.

  • 150. Mahajan, Anubha
    et al.
    Go, Min Jin
    Zhang, Weihua
    Below, Jennifer E
    Gaulton, Kyle J
    Ferreira, Teresa
    Horikoshi, Momoko
    Johnson, Andrew D
    Ng, Maggie C Y
    Prokopenko, Inga
    Saleheen, Danish
    Wang, Xu
    Zeggini, Eleftheria
    Abecasis, Goncalo R
    Adair, Linda S
    Almgren, Peter
    Atalay, Mustafa
    Aung, Tin
    Baldassarre, Damiano
    Balkau, Beverley
    Bao, Yuqian
    Barnett, Anthony H
    Barroso, Ines
    Basit, Abdul
    Been, Latonya F
    Beilby, John
    Bell, Graeme I
    Benediktsson, Rafn
    Bergman, Richard N
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Burtt, Noel
    Cai, Qiuyin
    Campbell, Harry
    Carey, Jason
    Cauchi, Stephane
    Caulfield, Mark
    Chan, Juliana C N
    Chang, Li-Ching
    Chang, Tien-Jyun
    Chang, Yi-Cheng
    Charpentier, Guillaume
    Chen, Chien-Hsiun
    Chen, Han
    Chen, Yuan-Tsong
    Chia, Kee-Seng
    Chidambaram, Manickam
    Chines, Peter S
    Cho, Nam H
    Cho, Young Min
    Chuang, Lee-Ming
    Collins, Francis S
    Cornelis, Marilyn C
    Couper, David J
    Crenshaw, Andrew T
    van Dam, Rob M
    Danesh, John
    Das, Debashish
    de Faire, Ulf
    Dedoussis, George
    Deloukas, Panos
    Dimas, Antigone S
    Dina, Christian
    Doney, Alex S F
    Donnelly, Peter J
    Dorkhan, Mozhgan
    van Duijn, Cornelia
    Dupuis, Josee
    Edkins, Sarah
    Elliott, Paul
    Emilsson, Valur
    Erbel, Raimund
    Eriksson, Johan G
    Escobedo, Jorge
    Esko, Tonu
    Eury, Elodie
    Florez, Jose C
    Fontanillas, Pierre
    Forouhi, Nita G
    Forsen, Tom
    Fox, Caroline
    Fraser, Ross M
    Frayling, Timothy M
    Froguel, Philippe
    Frossard, Philippe
    Gao, Yutang
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Grallert, Harald
    Grant, George B
    Groop, Leif C
    Groves, Christopher J
    Grundberg, Elin
    Guiducci, Candace
    Hamsten, Anders
    Han, Bok-Ghee
    Hara, Kazuo
    Hassanali, Neelam
    Hattersley, Andrew T
    Hayward, Caroline
    Hedman, Asa K
    Herder, Christian
    Hofman, Albert
    Holmen, Oddgeir L
    Hovingh, Kees
    Hreidarsson, Astradur B
    Hu, Cheng
    Hu, Frank B
    Hui, Jennie
    Humphries, Steve E
    Hunt, Sarah E
    Hunter, David J
    Hveem, Kristian
    Hydrie, Zafar I
    Ikegami, Hiroshi
    Illig, Thomas
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Islam, Muhammed
    Isomaa, Bo
    Jackson, Anne U
    Jafar, Tazeen
    James, Alan
    Jia, Weiping
    Jockel, Karl-Heinz
    Jonsson, Anna
    Jowett, Jeremy B M
    Kadowaki, Takashi
    Kang, Hyun Min
    Kanoni, Stavroula
    Kao, Wen Hong L
    Kathiresan, Sekar
    Kato, Norihiro
    Katulanda, Prasad
    Keinanen-Kiukaanniemi, Sirkka M
    Kelly, Ann M
    Khan, Hassan
    Khaw, Kay-Tee
    Khor, Chiea-Chuen
    Kim, Hyung-Lae
    Kim, Sangsoo
    Kim, Young Jin
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Korpi-Hyovalti, Eeva
    Kowlessur, Sudhir
    Kraft, Peter
    Kravic, Jasmina
    Kristensen, Malene M
    Krithika, S
    Kumar, Ashish
    Kumate, Jesus
    Kuusisto, Johanna
    Kwak, Soo Heon
    Laakso, Markku
    Lagou, Vasiliki
    Lakka, Timo A
    Langenberg, Claudia
    Langford, Cordelia
    Lawrence, Robert
    Leander, Karin
    Lee, Jen-Mai
    Lee, Nanette R
    Li, Man
    Li, Xinzhong
    Li, Yun
    Liang, Junbin
    Liju, Samuel
    Lim, Wei-Yen
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia M
    Lindholm, Eero
    Liu, Ching-Ti
    Liu, Jian Jun
    Lobbens, Stephane
    Long, Jirong
    Loos, Ruth J F
    Lu, Wei
    Luan, Jian'an
    Lyssenko, Valeriya
    Ma, Ronald C W
    Maeda, Shiro
    Magi, Reedik
    Mannisto, Satu
    Matthews, David R
    Meigs, James B
    Melander, Olle
    Metspalu, Andres
    Meyer, Julia
    Mirza, Ghazala
    Mihailov, Evelin
    Moebus, Susanne
    Mohan, Viswanathan
    Mohlke, Karen L
    Morris, Andrew D
    Muhleisen, Thomas W
    Muller-Nurasyid, Martina
    Musk, Bill
    Nakamura, Jiro
    Nakashima, Eitaro
    Navarro, Pau
    Ng, Peng-Keat
    Nica, Alexandra C
    Nilsson, Peter M
    Njolstad, Inger
    Nothen, Markus M
    Ohnaka, Keizo
    Ong, Twee Hee
    Owen, Katharine R
    Palmer, Colin N A
    Pankow, James S
    Park, Kyong Soo
    Parkin, Melissa
    Pechlivanis, Sonali
    Pedersen, Nancy L
    Peltonen, Leena
    Perry, John R B
    Peters, Annette
    Pinidiyapathirage, Janani M
    Platou, Carl G P
    Potter, Simon
    Price, Jackie F
    Qi, Lu
    Radha, Venkatesan
    Rallidis, Loukianos
    Rasheed, Asif
    Rathmann, Wolfgang
    Rauramaa, Rainer
    Raychaudhuri, Soumya
    Rayner, N William
    Rees, Simon D
    Rehnberg, Emil
    Ripatti, Samuli
    Robertson, Neil
    Roden, Michael
    Rossin, Elizabeth J
    Rudan, Igor
    Rybin, Denis
    Saaristo, Timo E
    Salomaa, Veikko
    Saltevo, Juha
    Samuel, Maria
    Sanghera, Dharambir K
    Saramies, Jouko
    Scott, James
    Scott, Laura J
    Scott, Robert A
    Segre, Ayellet V
    Sehmi, Joban
    Sennblad, Bengt
    Shah, Nabi
    Shah, Sonia
    Shera, A Samad
    Shu, Xiao Ou
    Shuldiner, Alan R
    Sigurðsson, Gunnar
    Sijbrands, Eric
    Silveira, Angela
    Sim, Xueling
    Sivapalaratnam, Suthesh
    Small, Kerrin S
    So, Wing Yee
    Stancakova, Alena
    Stefansson, Kari
    Steinbach, Gerald
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Strawbridge, Rona J
    Stringham, Heather M
    Sun, Qi
    Suo, Chen
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Takayanagi, Ryoichi
    Takeuchi, Fumihiko
    Tay, Wan Ting
    Teslovich, Tanya M
    Thorand, Barbara
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Tikkanen, Emmi
    Trakalo, Joseph
    Tremoli, Elena
    Trip, Mieke D
    Tsai, Fuu Jen
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Valladares-Salgado, Adan
    Vedantam, Sailaja
    Veglia, Fabrizio
    Voight, Benjamin F
    Wang, Congrong
    Wareham, Nicholas J
    Wennauer, Roman
    Wickremasinghe, Ananda R
    Wilsgaard, Tom
    Wilson, James F
    Wiltshire, Steven
    Winckler, Wendy
    Wong, Tien Yin
    Wood, Andrew R
    Wu, Jer-Yuarn
    Wu, Ying
    Yamamoto, Ken
    Yamauchi, Toshimasa
    Yang, Mingyu
    Yengo, Loic
    Yokota, Mitsuhiro
    Young, Robin
    Zabaneh, Delilah
    Zhang, Fan
    Zhang, Rong
    Zheng, Wei
    Zimmet, Paul Z
    Altshuler, David
    Bowden, Donald W
    Cho, Yoon Shin
    Cox, Nancy J
    Cruz, Miguel
    Hanis, Craig L
    Kooner, Jaspal
    Lee, Jong-Young
    Seielstad, Mark
    Teo, Yik Ying
    Boehnke, Michael
    Parra, Esteban J
    Chambers, John C
    Tai, E Shyong
    McCarthy, Mark I
    Morris, Andrew P
    Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 3, s. 234-244Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

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