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  • 251.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Comment on JIM-16-0640.R1. "Mortality from aortic stenosis - prospective study of serum calcium and phosphate' by D. Wald2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 4, p. 412-413Article in journal (Other academic)
    Abstract [en]

    .

  • 252.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Endothelium-dependent vasodilation predicts the development of the metabolic syndrome2015In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 35, no 6, p. 411-417Article in journal (Refereed)
    Abstract [en]

    Background: Different techniques to evaluate endothelium-dependent vasodilation (EDV) in resistance and conduit arteries have been described and have been associated with the occurrence of the metabolic syndrome (MetS) in cross-sectional studies. This study aimed to evaluate whether EDV in resistance and conduit arteries could predict future development of the MetS in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. Methods: In the population-based PIVUS study (1016 subjects all aged 70 at baseline), the invasive forearm technique with acetylcholine given in the brachial artery (resistance arteries, EDV) and the brachial artery ultrasound technique with the measurement of flow-mediated dilatation (conduit artery, FMD) were evaluated. Six hundred and twenty-four subjects free of the MetS (NCEP/ATPIII criteria) at the age of 70 were reinvestigated at the age of 75. Results: During the 5-year follow-up, 109 new subjects developed the MetS. EDV, but not FMD, predicted the development of the MetS (OR 0.78 for a 1 SD increase in EDV, 95% CI 0.62-0.97, P = 0.033). Of the five components of the MetS, EDV could significantly predict the development of the glucose (P = 0.02), waist circumference (P = 0.01) and the triglyceride components (P = 0.002), but not significantly so the HDL (P = 0.09) and blood pressure components (P = 0.92). Conclusions: EDV in resistance arteries, but not in the brachial conduit artery (FMD), was a predictor of future development of the MetS, mainly by prediction of future impairments in fasting glucose, serum triglycerides and waist circumference in an elderly cohort.

  • 253.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Flow-mediated vasodilation over five years in the general elderly population and its relation to cardiovascular risk factors2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 237, no 2, p. 666-670Article in journal (Refereed)
    Abstract [en]

    Background: Flow-mediated vasodilation (FMD) has previously been shown to be related to cardiovascular risk factors in cross-sectional studies. The present study aims to investigate how FMD changes over time, and determine whether this change is paralleled by changes in cardiovascular risk factors. Methods: Of the participants in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 750 individuals had measurements made of FMD in the brachial artery both at the ages of 70 and 75 years. In addition, the change over the 5 years in carotid artery intima-media thickness (IMT) was monitored, as well as traditional cardiovascular risk factors. Results: While no significant change in FMD occurred during the 5-year period (+0.1%, p = 0.53), large changes could be seen at the individual level. The Framingham risk score (excluding the age-variable) increased during the follow-up period (+0.54, p < 0.001). This change was inversely related to the individual change in FMD (beta -0.15, 95% CI -0.29 to 0.0059, p = 0.041). Of the eight individual CV risk factors tested, the change in FMD was only related to the change in LDL-cholesterol (inversely, p = 0.0028). The change in FMD was not related to the change in IMT seen over the 5-year period (p = 0.41). Conclusion: While no change was seen in the mean FMD over a five-year period in elderly subjects attending both examinations despite ageing and a change in several risk factors, the individual change was mainly related to the change in LDL-cholesterol, further emphasizing the important role of lipids to determine vasoreactivity.

  • 254.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Flow-Mediated Vasodilation was Found to be an Independent Predictor of Changes in the Carotid Plaque Status During a 5-Year Follow-Up: A Prospective Investigation of the Vasculature in the Uppsala Seniors (PIVUS) Study2014In: Journal of Atherosclerosis and Thrombosis, ISSN 1880-3873, E-ISSN 1340-3478, Vol. 21, no 2, p. 161-168Article in journal (Refereed)
    Abstract [en]

    Aim: It has previously been shown that flow-mediated vasodilation is a predictor of the progression of the intima-media thickness (IMT). In the present study, the degree of endothelium-dependent vasodilation in both resistance and conduit arteries was evaluated as a predictor of the IMT and plaque progression. Methods: In the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) trial (1,016 subjects all 70 years of age), the invasive forearm technique using acetylcholine administered in the brachial artery (resistance artery, EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (conduit artery, FMD) were evaluated. The IMT and number of carotid arteries with plaques (0, 1 or 2) were recorded using ultrasound at the baseline investigation and the follow-up visit conducted five years later. Results: A total of 760 subjects had valid measurements of the IMT and carotid artery plaques at both the investigations conducted at 70 and 75 years of age. Neither the FMD nor EDV significantly predicted the change in IMT over five years. However, the FMD, but not EDV, was associated with the change in carotid plaque burden during the follow-up period, independent of classical risk factors, such as gender, waist circumference, fasting blood glucose, systolic and diastolic blood pressure, HDL- and LDL-cholesterol, serum triglycerides, BMI and smoking (OR 0.81 for a 1 SD change in FMD, 95% CI 0.68 to 0.95, p=0.010). Conclusions: The FMD was found to be a predictor of changes in the carotid plaque status, but not IMT, during the 5-year follow-up period, independent of classical cardiovascular risk factors.

  • 255.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Relationships between three different tests to evaluate endothelium-dependent vasodilation and cardiovascular risk in a middle-aged sample2013In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 31, no 8, p. 1570-1574Article in journal (Refereed)
    Abstract [en]

    Objective:

    For a couple of decades, flow-mediated vasodilation in the brachial artery (FMD) and acetylcholine-mediated vasodilation in the forearm (EDV) have been used to assess endothelium-dependent vasodilation. During recent years a third technique, peripheral artery tonometry (PAT) using EndoPat, has been introduced. We now aimed to investigate the relationships between these techniques, and their relation to cardiovascular risk.

    Methods:

    In the population-based Prospective investigation of Obesity, Energy and Metabolism (POEM) study conducted in individuals all aged 50 years (50% women), EDV, FMD and the reactive hyperemia index were measured in the first 222 individuals. Cardiovascular risk was assessed by the Framingham risk score.

    Results:

    No significant relationships were seen between the three different tests to evaluate endothelium-dependent vasodilation. EDV (r=-0.21, P=0.004) and FMD (r=-0.19, P=0.004), but not PAT were significantly related to the Framingham score in an inverse way. Also sodium nitroprusside-mediated vasodilation in the forearm, reflecting endothelium-independent vasodilation (EIDV), was related to the Framingham score in an inverse way (r=-0.30, P<0.0001).

    Conclusion:

    No close relationships were seen between the three tests of endothelium-dependent vasodilation, suggesting that they each contribute with unique information on vasoreactivity. EDV, EIDV and FMD, but not PAT, were related to the Framingham score, suggesting that vasoreactivity in some vascular beds are related to cardiovascular risk in middle-aged individuals.

  • 256.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carlsson, Axel C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Alfred Nobels Alle 23, S-14152 Huddinge, Sweden..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Dalarna Univ, Dept Hlth & Social Sci, S-79188 Falun, Sweden..
    Impact of physical activity on cardiovascular status in obesity2017In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 47, no 2, p. 167-175Article in journal (Refereed)
    Abstract [en]

    Background We have recently shown that being physically active (PA) counteracts, but not eliminates the increased risk of future cardiovascular disease in overweight and obese subjects. To investigate this further, we studied the impact of being normal weight, overweight and obese on multiple markers of subclinical cardiovascular disease in relation to physical activity. Materials and methods At age 70, 1016 subjects were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Being PA was defined as performing regular heavy exercise (self-reported). According to body mass index (BMI)/PA groups, the participants were categorized as PA/normal weight (BMI < 25 kg/m(2), n = 104), non-PA/normal weight (n = 234), PA/overweight (BMI 25-29.9 kg/m(2), n = 133), non-PA/overweight (n = 295), PA/obese (BMI = 30 kg/m(2), n = 54) and non-PA/obese (n = 169). Several different measurements of endothelial reactivity and arterial compliance (plethysmography and ultrasound), cartotid artery atherosclerosis and echocardiography were performed, and seven markers of coagulation/ fibrinolysis were measured. Results Physically active subjects with obesity showed impaired vasoreactivity in the forearm resistance vessels, increased left ventricular mass and impaired left ventricular systolic and diastolic functions, together with impaired coagulation/fibrinolysis when compared to PA/normal-weight subjects (P < 0.05 to < 0.001). The majority of these disturbances were seen also in PA/overweight subjects when compared to PA/normal-weight subjects (P < 0.05 to < 0.001). Conclusions Our data provide additional support for the notion that an increased level of self-reported physical activity does not fully eliminate the deleterious cardiovascular consequences associated with overweight and obesity.

  • 257.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Elmstahl, Solve
    Bergman, Ebba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Englund, Martin
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Peter M.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    EpiHealth: a large population-based cohort study for investigation of gene-lifestyle interactions in the pathogenesis of common diseases2013In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 28, no 2, p. 189-197Article in journal (Refereed)
    Abstract [en]

    The most common diseases affecting middle-aged and elderly subjects in industrialized countries are multigenetic and lifestyle related. Several attempts have been made to study interactions between genes and lifestyle factors, but most such studies lack the power to examine interactions between several genes and several lifestyle components. The primary objective of the EpiHealth cohort study is to provide a resource to study interactions between several genotypes and lifestyle factors in a large cohort (the aim is 300,000 individuals) derived from the Swedish population in the age range of 45-75 years regarding development of common degenerative disorders, such as cardiovascular diseases, cancer, dementia, joint pain, obstructive lung disease, depression, and osteoporotic fractures. The study consists of three parts. First, a collection of data on lifestyle factors by self-assessment using an internet-based questionnaire. Second, a visit to a test center where blood samples are collected and physiological parameters recorded. Third, the sample is followed for occurrence of outcomes using nationwide medical registers. This overview presents the study design and some baseline characteristics from the first year of data collection in the EpiHealth study.

  • 258.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Dept Hlth Sci, Div Geriatr Med, Malmo, Sweden..
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Change in Body Weight from Age 20 Years Is a Powerful Determinant of the Metabolic Syndrome2017In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 3, p. 112-117Article in journal (Refereed)
    Abstract [en]

    Background: Higher body weight is a well-known determinant of the metabolic syndrome (MetS) and its components. It is however less well studied how the change in weight from age 20 years to middle age or old age affects MetS development. Methods: In the community-based EpiHealth (n = 19,000, age range 45 to 75 years, 56% females) and PIVUS (n = 1000, all aged 70 years, 50% females) studies, the participants were asked about their body weight at age 20 years. Data were collected to determine MetS prevalence (NCEP ATP III criteria). Results: In EpiHealth, the probability of having MetS increased fairly linearly with increasing weight from age 20 in the obese [odds ratios (OR) 1.04 per kg change in weight, 95% confidence interval (CI) 1.03-1.05, P < 0.0001], as well as in the overweight (OR 1.15, 95% CI 1.14-1.17, P < 0.0001) and normal-weight (OR 1.18, 95% CI 1.14-1.21, P < 0.0001), subjects after adjustment for age, sex, body mass index (BMI) at age 20, alcohol intake, smoking, education, and exercise habits. Also in the PIVUS study, the change in weight over 50 years was related to prevalent MetS (OR 1.08 per kg change in weight, 95% CI 1.06-1.10, P < 0.0001). In both studies, self-reported BMI at age 20 was related to prevalent MetS. Conclusion: Self-reported weight gain from age 20 was strongly and independently associated with prevalent MetS both in middle age or old age. Interestingly, this relationship was not restricted only to obese subjects. Our data provide additional support for the importance of maintaining a stable weight throughout life.

  • 259.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hulthe, J.
    Johansson, A.
    Hedner, E.
    Endotoxin-induced and vaccine-induced systemic inflammation both impair endothelium-dependent vasodilation, but not pulse wave reflection2012In: Vascular health and risk management, ISSN 1178-2048, Vol. 8, p. 447-453Article in journal (Refereed)
    Abstract [en]

    Inflammation induced by either endotoxin or vaccination has previously been shown to impair endothelium-dependent vasodilation (EDV) in healthy young individuals. However, the vascular effects of these two mechanisms of inducing inflammation have not been compared in the same individuals. Twelve young healthy males were studied at the same time of the day on three occasions in a random order; on one occasion 4 hours following an endotoxin injection (Escherichia coli endotoxin, 20 IU/kg), on another occasion 8 hours following vaccination against Salmonella typhi, and on a third occasion 4 hours following a saline control injection. EDV and endothelium-independent vasodilation (EIDV) were evaluated by local infusions of acetylcholine and sodium nitroprusside in the brachial artery, and forearm blood flow was measured with venous occlusion plethysmography. The augmentation index was determined by pulse wave analysis as an index of pulse wave reflection. Both endotoxin and vaccination impaired EDV to a similar degree compared with the saline control (P = 0.005 and P = 0.014, respectively). EIDV was not significantly affected by inflammation. Endotoxin, but not vaccination, increased body temperature and circulating levels of intracellular adhesion molecule-1 and interleukin-6. Augmentation index was not affected by the interventions. Despite the fact that endotoxin induced a more pronounced degree of inflammation than vaccination, both inflammatory challenges impaired EDV to a similar degree, supporting the view that different inflammatory stimuli could induce harmful effects on the vasculature.

  • 260.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Teerlink, Tom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation2013In: Vascular Medicine, ISSN 1358-863X, E-ISSN 1477-0377, Vol. 18, no 4, p. 192-199Article in journal (Refereed)
    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.

  • 261.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Methylation-based estimated biological age and cardiovascular disease2018In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, no 2, article id e12872Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DNA methylation changes over life at specific sites in the genome, which can be used to estimate "biological age." The aim of this population-based longitudinal cohort study was to investigate the association between estimated biological age and incident cardiovascular disease (CVD).

    MATERIALS AND METHODS: Based on formulas published by Hannum et al and Horvath et al, "biological age" was calculated using data from the Illumina 450k Bead Methylation chip in 832 participants free from cardiovascular disease in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between estimated biological and chronological age was calculated (DiffAge).

    RESULTS: During 10 years of follow-up, 153 incident cases of cardiovascular disease occurred. In the sex-adjusted analyses, the Horvath estimation of DiffAge was significantly related to incident cardiovascular disease (HR 1.040, 95% CI 1.010-1.071, P = .0079). Thus, for each year of increased biological age, a 4% increased risk of future cardiovascular disease was observed. This relationship was still significant following adjustment for the traditional risk factors sex, BMI, diabetes, HDL and LDL-cholesterol, systolic blood pressure and smoking (HR 1.033, 95% CI 1.004-1.063, P = .024). No such significant association was found using the Hannum formula.

    CONCLUSIONS: DNA methylation-based estimation of "biological age" per Horvath was associated with incident cardiovascular disease.

  • 262.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lejonklou, Margareta H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Bergman, Åke
    Guerrero-Bosagna, Carlos
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lee, Hong Kyu
    Legler, Juliette
    Nadal, Angel
    Pak, Youngmi Kim
    Phipps, Richard P
    Vandenberg, Laura N
    Zalko, Daniel
    Ågerstrand, Marlene
    Öberg, Mattias
    Blumberg, Bruce
    Heindel, Jerrold J
    Birnbaum, Linda S
    Uppsala Consensus Statement on Environmental Contaminants and the Global Obesity Epidemic2016In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 124, no 5, p. A81-A83Article in journal (Refereed)
    Abstract [en]

    From the lectures presented at the 2nd International Workshop on Obesity and Environmental Contaminants, which was held in Uppsala, Sweden, on 8–9 October 2015, it became evident that the findings from numerous animal and epidemiological studies are consistent with the hypothesis that environmental contaminants could contribute to the global obesity epidemic. To increase awareness of this important issue among scientists, regulatory agencies, politicians, chemical industry management, and the general public, the authors summarize compelling scientific evidence that supports the hypothesis and discuss actions that could restrict the possible harmful effects of environmental contaminants on obesity.

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    fulltext
  • 263.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ng, Esther
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based sample2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, p. 212-218Article in journal (Refereed)
    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.

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  • 264.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Endothelium-dependent vasodilation is related to the occurrence of cortical brain infarcts at MR imaging: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study2017In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 37, no 2, p. 194-197Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Infarcts in the brain can be divided into larger cortical and smaller deep lacunar infarcts. The pathogenesis differs between these two types of infarctions.

    OBJECTIVE: This study aims to investigate the relationship between measures of endothelium-dependent vasodilation (EDV) and occurrence of cortical and lacunar infarcts in a population-based sample.

    METHODS: In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV) and brachial artery ultrasound to assess flow-mediated vasodilation (FMD). Six to seven years later MRI of the brain was performed, and the prevalence of cortical and lacunar infarcts was visually assessed in 407 randomly selected subjects.

    RESULTS: Lacunar infarcts were found in 22% and cortical infarcts in 5·9% of the subjects. EDV and FMD were both significantly related to the occurrence of cortical, but not lacunar infarcts. In a model adjusting for gender, waist circumference, body mass index, fasting blood glucose, systolic and diastolic blood pressure, HDL and LDL cholesterol, serum triglycerides, smoking, antihypertensive treatment and statin use, both EDV and FMD were independent predictors of cortical infarcts (P = 0·035 and P = 0·008, respectively).

    CONCLUSIONS: Endothelium-dependent vasodilation in both forearm resistance vessels and the brachial artery was related to the occurrence of cortical, but not lacunar, infarcts at MRI in a population-based sample independently of traditional risk factors.

  • 265.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Luttropp, Karin
    Nordfors, Louise
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    van Bavel, Bert
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population2013In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 59, p. 456-461Article in journal (Refereed)
    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.

  • 266.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Salihovic, Samira
    van Bavel, Bert
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 133, p. 135-140Article in journal (Refereed)
    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.

  • 267.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Peters, Sanne A. E.
    den Ruijter, Hester M.
    Palmer, Mike K.
    Grobbee, Diederick E.
    Crouse, John R., III
    O'Leary, Daniel H.
    Evans, Gregory W.
    Raichlen, Joel S.
    Bots, Michiel L.
    Effect of Rosuvastatin on the Echolucency of the Common Carotid Intima-Media in Low-Risk Individuals: the METEOR Trial2012In: Journal of the American Society of Echocardiography, ISSN 0894-7317, E-ISSN 1097-6795, Vol. 25, no 10, p. 1120-1127.e1Article in journal (Refereed)
    Abstract [en]

    Background:

    The echolucency of the carotid intima-media is related to increased cardiovascular risk factor levels, morbidity, and mortality. The aim of this study was to assess the effect of statins on the echolucency of the common carotid intima-media in a low-risk population.

    Methods:

    Data from the Measuring Effects on Intima-Media Thickness: An Evaluation of Rosuvastatin study were used. Ultrasound images from the far walls of the left and right common carotid arteries were used for evaluation of the echolucency of the carotid intima-media, measured by grayscale median (GSM). Low GSM values reflect echolucent structures, whereas high values reflect echogenic structures. The primary end point was the difference in the annual rate of change in GSM between rosuvastatin and placebo.

    Results:

    Two-year change in GSM did not significantly differ between rosuvastatin and placebo in the total population, with a mean difference in the rate of change in GSM of 1.13 (95% confidence interval, -1.00 to 3.25). The effect of rosuvastatin differed across quintiles of baseline GSM values (P for interaction = .01). In the lowest quintile (n = 175) (i.e., in those with the most echolucent intima-media), the difference in the rate of change in GSM between rosuvastatin and placebo was 4.18 (95% confidence interval, -0.23 to 8.58). Increases in GSM were significantly related to decreasing low-density lipoprotein cholesterol levels in the lowest quintile (beta = 0.76; 95% confidence interval, 0.26 to 1.25).

    Conclusions:

    Treatment with rosuvastatin did not affect the echolucency of the arterial wall in all low-risk individuals. However, a potential effect of rosuvastatin on the echolucency of the common carotid intima-media is most likely to be found in individuals with echolucent arterial walls at baseline.

  • 268.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Mixture effects of 30 environmental contaminants on incident metabolic syndrome: A prospective study2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 107, p. 8-15Article in journal (Refereed)
    Abstract [en]

    Background: Several cross-sectional studies have linked different environmental contaminants to the metabolic syndrome (MetS). However, mixture effects have not been investigated and no prospective studies exist regarding environmental contaminants and the MetS.

    Objectives: To study mixture effects of contaminants on the risk of incident MetS in a prospective fashion.

    Methods: Our sample consisted of 452 subjects from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years) free from the MetS at baseline, being followed for 10 years. At baseline, 30 different environmental contaminants were measured; 6 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, one dioxin, one polybrominated diphenyl ether (all in plasma), 8 perfluoroalkyl substances (in plasma) and 11 metals (in whole blood). The MetS was defined by the ATPIII/NCEP criteria. Gradient boosted Classification and Regression Trees (CARTs) was used to evaluate potential synergistic and additive mixture effects on incident MetS.

    Results: During 10-year follow-up, 92 incident cases of the MetS occurred. PCB126, PCB170, hexachlorobenzene (HCB) and PCB118 levels were all associated with incident MetS in an additive fashion (OR 1.73 for a change from 10th to 90th percentile (95% CI 1.24-3.04) for PCB126, OR 0.63 (0.42-0.78) for PCB170, OR 1.44 (1.09-2.20) for HCB and OR 1.46 (1.13-2.43) for PCB118). No synergistic effects were found.

    Conclusion: A mixture of environmental contaminants, with PCB126, PCB170, HCB and PCB118 being the most important, showed associations with future development of the MetS in an additive fashion in this prospective study. Thus, mixture effects of environmental contaminants could contribute to the development of cardiometabolic derangements.

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  • 269.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Stenemo, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip2015In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 46, no 12, p. 3340-3347Article in journal (Refereed)
    Abstract [en]

    Background and Purpose-Emerging technologies have made it possible to simultaneously evaluate a large number of circulating proteins as potential new stroke risk markers. Methods-We explored associations between 85 cardiovascular proteins, assessed by a proteomics chip, and incident ischemic stroke in 2 independent cohorts of elderly (Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS]: n=977; 50% women, mean age=70.1 years, 71 fatal/nonfatal ischemic stroke events during 10.0 years; and Uppsala Longitudinal Study in Adult Men [ULSAM]: n=720, mean age=77.5 years, 75 ischemic stroke events during 9.5 years). The proteomics chip uses 2 antibodies for each protein and a polymerase chain reaction step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations. Results-In PIVUS, 16 proteins were related to incident ischemic stroke using a false discovery rate of 5%. Of these, N-terminal pro-B-type natriuretic peptide (P=0.0032), adrenomedullin (P=0.018), and eosinophil cationic protein (P=0.0071) were replicated in ULSAM after adjustment for established stroke risk factors. In predefined secondary meta-analyses of individual data, interleukin-27 subunit , growth/differentiation factor 15, urokinase plasminogen activator surface receptor, tumor necrosis factor receptor superfamily member 6, macrophage colony-stimulating factor 1, and matrix metalloproteinase-7 were also potential risk markers for ischemic stroke after adjustment for multiple comparisons (P<0.0006). The addition of N-terminal pro-B-type natriuretic peptide, adrenomedullin, and eosinophil cationic protein to a model with established risk factors increased the C-statistic from 0.629 to 0.689 (P=0.001). Conclusions-Our data suggest that large-scale proteomics analysis is a promising way of discovering novel biomarkers that could substantially improve the prediction of ischemic stroke.

  • 270.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Simon, Tabassome
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kotti, Salma
    Hansen, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Machecourt, Jacques
    Ninio, Ewa
    Tedgui, Alain
    Danchin, Nicolas
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Mallat, Ziad
    Circulating levels of secretory- and lipoprotein-associated phospholipase A2 activities: relation to atherosclerotic plaques and future all-cause mortality2012In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 33, no 23, p. 2946-54Article in journal (Refereed)
    Abstract [en]

    Aims

    Secretory- and lipoprotein-associated phospholipases A2 (sPLA2 and Lp-PLA2) are enzymes both suggested to be of importance for atherosclerosis. We investigated relationships between the activities of these enzymes in the circulation and atherosclerosis as well as future clinical events.

    Methods and results

    The population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study included 1016 randomly selected subjects, all aged 70. The prevalence of carotid artery plaques was recorded by ultrasound (n= 954), and arterial stenosis was assessed by whole-body magnetic resonance angiography (WBMRA, n= 302). Secretory-associated phospholipase A2 [odds ratio 1.23 for 1 SD increase, 95% confidence interval (CI): 1.05-1.44, P= 0.007], but not Lp-PLA2 (P= 0.26), activity was significantly related to carotid atherosclerosis and to the amount of stenosis at WBMRA (P= 0.006) following adjustment for multiple risk factors (waist circumference, serum triglycerides, body mass index, C-reactive protein, high density lipoprotein-C, low density lipoprotein-C, triglycerides, GFR, fasting glucose, blood pressure, statin use, and exercise habits). Secretory-associated phospholipase A2 [hazard ratio (HR) 1.45 for 1 SD increase, 95% CI: 1.15-1.84, P= 0.001], but not Lp-PLA2 (HR 0.95, P= 0.55), activity was a significant risk factor for all-cause mortality (114 had died) during 7.0 years follow-up after adjustment for the risk factors described above. In a sample of 1029 post-myocardial infarction (MI) patients (French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction), sPLA2 (adjusted HR 1.32 for 1 unit increase, 95% CI: 1.02-1.71, P= 0.036), but not Lp-PLA2 (HR 1.03, P= 0.90), activity predicted death or recurrent MI during 1-year follow-up (n= 136 cases).

    Conclusion

    sPLA2 activity was related to atherosclerosis and predicted all-cause mortality in a sample of elderly subjects, as well as death or MI in post-MI patients.

  • 271.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Impact of Aging on the Strength of Cardiovascular Risk Factors: A Longitudinal Study Over 40 Years2018In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, no 1, article id e007061Article in journal (Refereed)
    Abstract [en]

    Background-The knowledge of the impact of cardiovascular risk factors at different ages has mainly been based on different studies performed at different ages. This study aimed to investigate the change in impact of traditional cardiovascular risk factors over the aging process in subjects followed for 4 decades. Methods and Results-In the ULSAM (Uppsala Longitudinal Study of Adult Men) study, 2322 men originally investigated in 1970 to 1974 have been followed regarding cardiovascular diseases until the end of 2013. This cohort has been investigated physically at ages 50, 60, 70, 77, and 82 years regarding body mass index, low-density lipoprotein-and high-density lipoprotein-cholesterol, triglycerides, systolic blood pressure and diastolic blood pressure, fasting glucose, and smoking. These data were used to model the interactions between risk factors and age regarding incident myocardial infarction (n=540), ischemic stroke (n=343), or heart failure (n=397). Significant interactions were observed between age and the set of traditional risk factors regarding all 3 outcomes (P<0.05 for all). Generally, a decline in the rate ratios was seen with aging for most risk factors, being most pronounced for body mass index regarding myocardial infarction and for systolic blood pressure regarding ischemic stroke and heart failure. However, low-density lipoprotein-cholesterol was significantly related to incident myocardial infarction, whereas both body mass index and fasting glucose were significantly related to incident heart failure also at a high age. Conclusions-Using a longitudinal design in middle-aged men spanning 4 decades showed that the impact of traditional cardiovascular risk factors generally declined with aging. However, some of the risk factors remained significantly associated with incident cardiovascular disease also at old age.

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  • 272.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hagg, S.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population2013In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 208, no 1, p. 88-94Article in journal (Refereed)
    Abstract [en]

    Aim Indirect evidences by blockade of the endothelin receptors have suggested a role of endothelin in endothelium-dependent vasodilation. This study aimed to investigate whether circulating levels of endotehlin-1 or genetic variations in genes in the endothelin pathway were related to endothelium-dependent vasodilation. Methods In 1016 seventy-year-old participants of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery (EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma endothelin-1 levels were measured and 60 SNPs in genes in the endothelin pathway (ECE1, EDN1, EDNRA, EDNRB) were genotyped. Results No significant associations were found between circulating endothelin levels and EDV or FMD. No single genotype was related to EDV or FMD following adjustment for multiple testing, but a genotype score for 3 SNPs (rs11618266 in EDNRB, rs17675063 in EDNRA, rs3026868 in ECE1) was significantly related to EDV (beta coefficient 0.070, 95% CI 0.0250.12, P=0.002) when adjusting for gender, systolic blood pressure, HDL and LDL cholesterol, serum triglycerides, BMI, diabetes, smoking, antihypertensive medication or statins and CRP. This score was also related to nitroprusside-induced vasodilation in the forearm. Conclusion A combination of genotypes in the endothelin pathway was related to both endothelium-dependent and endothelium-independent vasodilation in forearm resistance vessels, but not in the brachial artery in an elderly population, giving evidence for a role of the endothelin system in resistance vessel reactivity independent of major cardiovascular risk factors.

  • 273.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Wohlin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Andrén, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    The echogenicity of the intimamedia complex in the common carotid artery is related to insulin resistance measured by the hyperinsulinemic clamp in elderly men2013In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 33, no 2, p. 137-142Article in journal (Refereed)
    Abstract [en]

    The echogenicity of the intimamedia complex (IM-GSM) has recently been shown to be related to the echogenicity in carotid artery plaque and to predict cardiovascular (CV) mortality. The present study aims to evaluate the relationship between metabolic CV risk factors, with special emphasis on insulin resistance, and IM-GSM in the carotid artery. Carotid artery ultrasound with grey-scale median analysis of the intimamedia complex, IM-GSM, was performed in a population sample of 480 men aged 75years. In these subjects, a euglycemic hyperinsulinemic clamp to investigate insulin resistance was performed together with measurements of conventional CV risk factors at the age of 70. The metabolic syndrome (MetS) was defined by the NCEP/ATPIII-criteria. In univariate analysis, IM-GSM in the common carotid artery was inversely correlated with the intimamedia thickness (IMT), body mass index (BMI), waist/hip ratio, fasting glucose, serum triglycerides, low HDL cholesterol and insulin resistance at the clamp (r=0 center dot 24, P<0 center dot 001). In multiple regression analysis, only insulin resistance at the clamp and BMI were independently related to IM-GSM. Subjects with the MetS (22%) showed a reduced IM-GSM when compared to those without (64 +/- 20 SD versus 68 +/- 19, P<0 center dot 05). Because the echogenicity of the intimamedia complex in the carotid artery is related to obesity and insulin resistance at clamp independently of IMT, this new vascular characteristic would serve as a marker of vascular alterations induced by insulin resistance and the MetS and has the advantage to be obtainable in almost all subjects.

  • 274.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Lind, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating levels of perfluoroalkyl substances and prevalent diabetes in the elderly2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 3, p. 473-479Article in journal (Refereed)
    Abstract [en]

    Several environmental contaminants, such as polychlorinated biphenyls, dioxins, bisphenol A and phthalates, have been linked to diabetes. We therefore investigated whether other kinds of contaminants, perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), are also associated with diabetes. The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study investigated 1,016 men and women aged 70 years. Seven PFAS were detected in almost all participant sera by ultra-high performance liquid chromatograph/tandem mass spectrometry. Diabetes was defined as use of hypoglycaemic agents or fasting glucose > 7.0 mmol/l. 114 people had diabetes. In the linear analysis, no significant relationships were seen between the seven PFAS and prevalent diabetes. However, inclusion of the quadratic terms of the PFAS revealed a significant non-linear relationship between perfluorononanoic acid (PFNA) and diabetes, even after adjusting for multiple confounders (OR 1.96, 95% CI 1.19, 3.22, p = 0.008 for the linear term and OR 1.25, 95% CI 1.08, 1.44, p = 0.002 for the quadratic term). Perfluorooctanoic acid (PFOA) also showed such a relationship (p = 0.01). PFOA was related to the proinsulin/insulin ratio (a marker of insulin secretion), but none of the PFAS was related to the HOMA-IR (a marker of insulin resistance) following adjustment for multiple confounders. PFNA was related to prevalent diabetes in a non-monotonic fashion in this cross-sectional study, supporting the view that this perfluoroalkyl substance might influence glucose metabolism in humans at the level of exposure seen in the general elderly population.

  • 275.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    The Interplay Between Fat Mass and Fat Distribution as Determinants of the Metabolic Syndrome Is Sex-Dependent2017In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 7, p. 337-343Article in journal (Refereed)
    Abstract [en]

    Background: Fat mass and fat distribution are major determinants of the metabolic syndrome (MetS), but the interplay between them has not been thoroughly investigated. In addition, fat mass and fat distribution are generally different in men than in women. We aimed to determine whether the interplay between fat mass and fat distribution regarding MetS and its components is sex-dependent using data from the large-scale population-based sample EpiHealth. Methods: Occurrence of MetS and its components was determined together with fat mass by bioimpedance in 19,094 participants in the EpiHealth sample [mean age 61 years (SD 8.5), 56% females]. MetS was defined by the NCEP/ATPIII-criteria. Results: MetS prevalence was 23.0%. Fat mass (percent of body weight) was more strongly related to MetS (and the number of MetS components) in men than in women (P<0.0001 for interaction term) and in those with a high compared with those with a low waist/hip ratio (WHR). This modulating effect of WHR on the fat mass versus MetS-relationship was more pronounced in women than in men (P<0.0001 for interaction term). When analyzing the MetS components one by one, fat mass was more closely related to all the individual MetS criteria in men than in women, except for the glucose criteria. Conclusions: Fat mass is more closely related to prevalent MetS in men than in women, but the modulating effect of an abdominal type of fat distribution on the fat mass versus MetS-relationship is stronger in women.

  • 276.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 242, no 1, p. 205-210Article in journal (Refereed)
    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.

  • 277.
    Lind, Monica P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lee, D. -H
    Jacobs, D. R.
    Salihovic, S.
    Bavel, B. V.
    Wolff, M. S.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating levels of persistent organic pollutants are related to retrospective assessment of life-time weight change2013In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 90, no 3, p. 998-1004Article in journal (Refereed)
    Abstract [en]

    Background: Persistent organic pollutants (POPs) have been suggested to be linked to obesity. We have previously shown that less-chlorinated PCBs were positively related to fat mass, while highly-chlorinated PCBs were inversely related to obesity.Objective: The aim of the present evaluation is to investigate the relationship between retrospective assessed life-time change in body weight (20-70. years) with circulating POP levels measured at age 70. years.Methods: 1016 subjects aged 70. years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUSs) study. 16 PCBs and 3 OC pesticides were analyzed using HRGC/HRMS. Current body weight was measured and participants self-reported their weight at age 20.Results: The average estimated weight change over 50. years was 14.4. kg. Both the sum of OC pesticide concentrations (4.3. kg more weight gain in quintile 5 vs. quintile 1, p< 0.0001) and the sum of the less-chlorinated PCBs were positively related to the estimated weight change (3.7. kg more weight gain in quintile 2 vs. quintile 1, non-linear relationship p=0.0015). In contrast, the sum of concentrations of highly-chlorinated PCBs were inversely related to estimated weight change (8.4. kg less weight gain in quintile 5 vs. quintile 1, p< 0.0001).Conclusion: High levels of OC pesticides and the less-chlorinated PCBs at age 70 were associated with a pronounced estimated weight change over the previous 50. years. However, the opposite was seen for highly-chlorinated PCBs. Differences in mode of action, toxicokinetics, non-linear relationships and reverse causation might explain these discrepancies.

  • 278.
    Lind, Monica P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Olsén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Elevated circulating levels of copper and nickel are found in elderly subjects with left ventricular hypertrophy2012In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 86, p. 66-72Article in journal (Refereed)
    Abstract [en]

    Identified risk factors for left ventricular hypertrophy (LVH) are hypertension, diabetes and obesity. However, since these risk factors only explain a part of the variation in left ventricular mass, we investigated if trace and heavy metals might also play a role in LVH. In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, left ventricular mass index (LVMI) and relative wall thickness (RWT) were determined by echocardiography together with eleven different trace and heavy metals in 993 subjects aged 70 years. Only copper levels were significantly related to LVMI following adjustment for sex, blood pressure, antihypertensive treatment, diabetes and body mass index (BMI) (p<0.0001). However, both copper (Cu) and nickel (Ni) were related to RWT following adjustment (p<0.0001). When divided into four geometric groups, both Cu and Ni were elevated in subjects with concentric remodelling and concentric LVH, but not in those with eccentric hypertrophy, when compared to subjects with a normal left ventricle. No relationships were found for zinc, aluminium, manganese, molybdenum, mercury, lead, cadmium, cobalt or chromium. Elevated levels of copper and nickel are found in elderly subjects with LVH, especially of the concentric type, following adjustment for known risk factors for LVH.

  • 279.
    Lind, Monica P.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating levels of p,p '-DDE are related to prevalent hypertension in the elderly2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 129, p. 27-31Article in journal (Refereed)
    Abstract [en]

    Background: Polychlorinated biphenyls (PCBs) and dioxin given to experimental animals increase the blood pressure. We therefore investigated if circulating levels of persistent organic pollutants (POPs) were related to hypertension in a population-based sample of men and women. Methods: One thousand and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Twenty-three POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Hypertension was defined as a systolic blood pressure >= 140 mmHg or a diastolic blood pressure >= 90 mmHg, and/or use of antihypertensive medication. Results: Seven hundred and thirty-two subjects (72%) showed hypertension. When the POPs were treated as continuous variables and adjusted for gender only, two PCBs with a low number of chlorine atoms (PCB 105 and 118) were related to prevalent hypertension. Also the OC pesticide p,p'-DDE was related to hypertension. The strongest of these associations was seen for p,p'-DDE (OR 135 for a 1 SD change, 95% CI 1.17-1.56, p < 0.0001). Following further adjustment also for BMI, smoking status, education level and exercise habits, only p,p'-DDE was still significantly related to hypertension (OR 1.23 for a 1 SD change, 95% CI 1.06-1.43, p=0.006). Conclusion: In this cross-sectional analysis of an elderly population, high levels of circulating levels of p,p'-DDE were associated with prevalent hypertension, further strengthening the experimental findings that POPs might influence blood pressure.

  • 280.
    Lind, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Univ Orebro, MTM Res Ctr, Sch Sci & Technol, SE-70182 Orebro, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    van Bavel, B.
    Univ Orebro, MTM Res Ctr, Sch Sci & Technol, SE-70182 Orebro, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating levels of perfluoroalkyl substances and biomarkers of liver function in a large population based sample of elderly men and women from Sweden2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S91-S91Article in journal (Other academic)
  • 281.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 7, p. 1495-1502Article, review/survey (Refereed)
    Abstract [en]

    The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found > 40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p'-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p'-DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p'-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking.

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  • 282.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Riserus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Salihovic, Samira
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    An environmental wide association study (EWAS) approach to the metabolic syndrome2013In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 55, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background: Environmental contaminants have previously been linked to components of the Metabolic Syndrome (MetS). However, exposure to environmental contaminants is in part determined by various lifestyle factors. Objective: Using an "Environmental Wide Association Study" (ELWAS) integrating environmental contaminants and lifestyle factors, we aimed to evaluate a possible additive role of both contaminants and lifestyle factors regarding MetS. Methods: 1016 subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. 43 environmental contaminants were measured in the circulation. Dietary records were used to evaluate 21 nutrients and the proportions of 13 fatty acids were determined in serum cholesterol esters to further quantify fat quality intake. Adding 5 other important lifestyle factors yielded together 76 environmental and lifestyle factors. MetS was defined by the NCEP/ATPIII-criteria. Results: 23% had MetS. Using cross-validation within the sample, fourteen environmental contaminants or lifestyle factors consistently showed a false discovery rate <0.05. When the major variables entered a multiple model, only p,p'-DDE levels (positive), PCB209 (inverse) and exercise habits (inverse) were together with a fatty acid pattern, with high levels of palmitic acid and oleic acid and low levels of linoleic acid, related to MetS (p<0.002 for all variables). Conclusion: Using a cross-sectional EWAS approach, certain environmental contaminants and lifestyle factors were found to be associated with prevalent metabolic syndrome in an additive fashion in an elderly population. 

  • 283.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Roos, Vendela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women2012In: Environmental Health, E-ISSN 1476-069X, Vol. 11, no 1, p. 21-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Phthalates, commonly used to soften plastic goods, are known PPAR-agonists affecting lipid metabolism and adipocytes in the experimental setting. We evaluated if circulating concentrations of phthalates were related to different indices of obesity using data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Data from both dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) were used.

    METHODS:

    1,016 subjects aged 70 years were investigated in the PIVUS study. Four phthalate metabolites were detected in the serum of almost all subjects (> 96%) by an API 4000 liquid chromatograph/tandem mass spectrometer. Abdominal MRI was performed in a representative subsample of 287 subjects (28%), and a dual-energy X-ray absorptiometry (DXA)-scan was obtained in 890 (88%) of the subjects two year following the phthalate measurements.

    RESULTS:

    In women, circulating concentrations of mono-isobutyl phthalate (MiBP) were positively related to waist circumference, total fat mass and trunk fat mass by DXA, as well as to subcutaneous adipose tissue by MRI following adjustment for serum cholesterol and triglycerides, education, smoking and exercise habits (all p < 0.008). Mono-methyl phthalate (MMP) concentrations were related to trunk fat mass and the trunk/leg-ratio by DXA, but less powerful than MiBP. However, no such statistically significant relationships were seen in men.

    CONCLUSIONS:

    The present evaluation shows that especially the phthalate metabolite MiBP was related to increased fat amount in the subcutaneous abdominal region in women measured by DXA and MRI two years later.

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  • 284.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. MTM Research Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    High plasma organochlorine pesticide levels are related to increased biological age as calculated by DNA methylation analysis2018In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 113, p. 109-113Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Organochlorine pesticides (OCPs) have been shown in the experimental setting to alter DNA methylation. Since DNA methylation changes during the life-span, formulas have been presented to calculate "DNA methylation age" as a measure of biological age.

    OBJECTIVES: We aimed to investigate if circulating levels of three OCPs were related to increased DNA methylation age METHODS: 71CpG DNA methylation age (Hannum formula) was calculated based on data from the Illumina 450 k Bead Methylation chip in 1000 subjects in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between DNA methylation age and chronological age was calculated (DiffAge). 2,2-bis (4-chlorophenyl)-1,1-dichloroethene (p,p'-DDE), hexachlorobenzene (HCB), and transnonachlor (TNC) levels were measured in plasma by high-resolution gas chromatography coupled mass spectrometry (HRGC-HRMS).

    RESULTS: Increased p,p'-DDE and TNC, but not HCB, levels were related to increased DiffAge both in sex and BMI-adjusted models, as well as in multiple adjusted models (sex, education level, exercise habits, smoking, energy and alcohol consumption and BMI) (p = 0.0051 and p = 0.011, respectively). No significant interactions between the OCPs and sex or BMI regarding DiffAge were found.

    CONCLUSION: In this cross-sectional study, increased levels of two out of three OCPs were related to increased DNA methylation age, further suggesting negative health effects in humans of these widespread environmental contaminants.

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  • 285.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Stubleski, Jordan
    Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Kärrman, Anna
    Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Changes in plasma levels of perfluoroalkyl substances (PFASs) are related to increase in carotid intima-media thickness over 10 years - a longitudinal study2018In: Environmental Health, E-ISSN 1476-069X, Vol. 17, article id 59Article in journal (Refereed)
    Abstract [en]

    Background: It has previously been reported that the environmental contaminants perfluoroalkyl substances (PFASs) are linked to atherosclerosis in cross-sectional studies. Since cross-sectional studies could be subject to reverse causation, the purpose of this study was to analyze if the longitudinal changes in PFASs during a 10-year follow-up were related to the change in carotid artery intima-media thickness (IMT, ultrasound) during the same period.

    Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 individuals were investigated at age 70; 826 of them were reinvestigated at age 75 and 602 at age 80 years. Eight different PFASs were measured in plasma by ultra-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and IMT was measured at all three time points. Random-effects mixed regression models were used to examine the associations over time.

    Results: IMT increased 0.058 mm during the 10-year period (p <0.0001). Following adjustment for baseline values of PFASs (age 70) and sex, the changes in plasma levels of 6 of the 8 measured PFASs were significantly related to the change in IMT over the 10-year follow-up period in a positive fashion (p <0.0062 using Bonferroni correction for 8 tests). Further adjustment for traditional cardiovascular (CV) risk factors (HDL and LDL cholesterol, smoking, systolic blood pressure, statin use, fasting glucose and serum triglycerides) affected these relationships only marginally.

    Conclusion: The change in plasma levels of several PFASs during 10 years was positively related to increase in IMT seen during the same period, giving prospective evidence that PFASs might interfere with the atherosclerotic process.

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  • 286.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating levels of perfluoroalkyl substances (PFASs) and carotid artery atherosclerosis2017In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 152, p. 157-164Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: During recent years, some persistent organic pollutants (POPs) have been linked to atherosclerosis. One group of POPs, the poly- and perfluoroalkyl substances (PFASs) have not been investigated with regard to atherosclerotic plaques.

    METHODS: Carotid artery atherosclerosis was assessed by ultrasound in 1016 subjects aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants' plasma by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS).

    RESULTS: No significant linear associations were observed between the PFASs and intima-media thickness (IMT), or the echogenicity in the intima-media complex (IM-GSM, a marker of lipid infiltration in the artery) when men and women were analyzed together. Neither was occurrence of carotid plaques related to PFASs levels. However, highly significant interactions were observed between some PFASs and sex regarding both IM-GSM and plaque prevalence. Perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), were all related to IM-GSM in a positive fashion in women (p=0.002-0.003), while these relationships were negative in men. The levels of PFUnDA were significantly related to carotid plaque in women (OR 1.59, 95%CI 1.03-2.43, p=0.03), but not in men (OR 0.93, 95%CI 0.62-1.42, p=0.75).

    CONCLUSIONS: In this cross-sectional study, a pronounced gender difference was observed regarding associations between some PFASs, especially the long-chain PFUnDA, and markers of atherosclerosis, with more pronounced relationships found in women. These findings suggest a sex-specific role for PFASs in atherosclerosis.

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  • 287.
    Lind, P. Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating Levels of Phthalate Metabolites Are Associated With Prevalent Diabetes in the Elderly2012In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 35, no 7, p. 1519-1524Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-Phthalates are ubiquitous industrial high-volume chemicals known as ligands to peroxisome proliferator activated receptors (PPARs). Because PPAR-gamma agonists modulate insulin sensitivity and are used to treat type 2 diabetes, we investigated whether circulating levels of phthalate metabolites are related to prevalent type 2 diabetes. RESEARCH DESIGN AND METHODS-A total of 1,016 subjects, aged 70 years, were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors Study. Four phthalate metabolites were detected in almost all participant sera by an API 4000 liquid chromatograph/tandem mass spectrometer. Type 2 diabetes was defined as the use of pharmacological hypoglycemic agents or a fasting plasma glucose >7.0 mmol/L. RESULTS-A total of 114 subjects were shown to have diabetes. Following adjustment for sex, BMI, serum cholesterol and triglycerides, educational level, and smoking and exercise habits, high levels of the phthalate metabolites monomethyl phthalate (MMP) (P < 0.01), monoisobutyl phthalate (MiBP) (P < 0.05), and monoethyl phthalate (MEP) (P < 0.05), but not mono(2-ethylhexyl) phthalate, were associated with an increased prevalence of diabetes. Using the fasting proinsulin to insulin ratio as a marker of insulin secretion and the homeostasis model assessment-insulin resistance index as a marker of insulin resistance, MiBP was mainly related to poor insulin secretion, whereas MEP and MMP mainly were related to insulin resistance. CONCLUSIONS-The findings in this cross-sectional study showed that several phthalate metabolites are related to diabetes prevalence, as well as to markers of insulin secretion and resistance. These findings support the view that these commonly used chemicals might influence major factors that are regulating glucose metabolism in humans at the level of exposure of phthalate metabolites seen in the general elderly population.

  • 288. Lind, Ylva Sjoberg
    et al.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Circulating levels of persistent organic pollutants (POPs) are associated with left ventricular systolic and diastolic dysfunction in the elderly2013In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 123, p. 39-45Article in journal (Refereed)
    Abstract [en]

    Background and objective: Major risk factors for congestive heart failure (CHF) are myocardial infarction, hypertension, diabetes, atrial fibrillation, smoking, left ventricular hypertrophy (LVH) and obesity. However, since these risk factors only explain part of the risk of CHF, we investigated whether persistent organic pollutants (POPs) might also play a role. Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, left ventricular ejection fraction, (EF), E/A-ratio and isovolumic relaxation time (IVRT), were determined by echocardiography and serum samples of 21 POPs were analyzed in serum measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 998 subjects all aged 70 years. Results: In this cross-sectional analysis, high levels of several of the polychlorinated biphenyls (PCB congeners 99, 118, 105, 138, 153, and 180) and octachlorodibenzo-p-dioxin (OCDD) were significantly related to a decreased EF. Some POPs were also related to a decreased E/A-ratio (PCBs 206 and 209). All the results were adjusted for gender, hypertension, diabetes, smoking, LVH and BMI, and subjects with myocardial infarction or atrial fibrillation were excluded from the analysis. Conclusions: Circulating levels of POPs were related to impairments in both left ventricular systolic and diastolic function independently of major congestive heart failure risk factors, suggesting a possible role of POPs in heart failure.

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  • 289. Lind, Ylva Sjoeberg
    et al.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    van Bavel, Bert
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Persistent organic pollutants and abnormal geometry of the left ventricle in the elderly2013In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 31, no 8, p. 1547-1553Article in journal (Refereed)
    Abstract [en]

    Background:

    Established risk factors for left ventricular hypertrophy (LVH) are hypertension, diabetes, and obesity. However, as these risk factors explain only part of the variation in left ventricular mass, we investigated whether persistent organic pollutants (POPs) might also play a role in LVH, because exposure to polychlorinated biphenyl 126 induced cardiac growth in rats.

    Methods:

    In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), left ventricular mass index (LVMI), relative wall thickness (RWT), and geometric groups of LVH, were determined by echocardiography and 21 POPs were measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 1016 individuals aged 70 years. All individuals with a history of myocardial infarction were excluded from analysis (n=72).

    Results:

    Several of the POPs were related to abnormal left ventricular geometry before adjustment for established risk factors, but lost in significance following adjustment. However, the pesticide hexachlorobenzene (HCB) levels were significantly related to RWT, and concentric left ventricular remodeling, also following adjustment for sex, blood pressure, antihypertensive treatment, diabetes, and BMI (P<0.0001).

    Conclusion:

    In this cross-sectional study, circulating levels of HCB were related to increased wall thickness of the left ventricle and concentric left ventricular remodeling, independently of LVH risk factors, suggesting a role of this environmental contaminant in abnormal growth of the left ventricle.

  • 290. Liu, C
    et al.
    Marioni, R E
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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.2018In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, p. 422-433Article in journal (Refereed)
    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.

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  • 291.
    Ljunggren, Gunnar
    et al.
    Stockholm Cty Council, Publ Healthcare Serv Comm Adm, Huddinge, Sweden.;Karolinska Inst, Dept Learning, Informat, Med Management Ctr,Management & Eth, Huddinge, Sweden..
    Wandell, Per
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Sandstrom, Ylva Kristoferson
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Wahlström, Lars
    Karolinska Inst, Ctr Psychiat Res, Stockholm, Sweden..
    Carlsson, Axel C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Depression in hypertensive patients: the role of comorbidities Reply2016In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 34, no 7, p. 1441-1442Article in journal (Refereed)
  • 292.
    Ljunggren, S. A.
    et al.
    Linkoping Univ, Occupat & Environm Med Ctr, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Iggland, M.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karlsson, H.
    Linkoping Univ, Occupat & Environm Med Ctr, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A2016In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 347-349, p. 6-16Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25 mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

  • 293. 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ferreira, Teresa
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 biology2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, no 7538, p. 197-206Article in journal (Refereed)
    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.

  • 294.
    Loley, Christina
    et al.
    Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Campus Lubeck, Lubeck, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany..
    Alver, Maris
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Inst Mol & Cell Biol, Tartu, Estonia..
    Assimes, Themistocles L.
    Stanford Univ, Sch Med Stanford, Dept Med, Div Cardiovasc Med, Stanford, CA USA..
    Bjonnes, Andrew
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Goel, Anuj
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Heart Hosp, Dept Cariol, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland..
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, CTSU, Oxford, England..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Lau, King Wai
    Univ Oxford, Nuffield Dept Populat Hlth, CTSU, Oxford, England..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Nikpay, Majid
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Qu, Liming
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Salfati, Elias
    Stanford Univ, Sch Med Stanford, Dept Med, Div Cardiovasc Med, Stanford, CA USA..
    Scholz, Markus
    Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, Leipzig, Germany.;LIFE Res Ctr Civilizat Dis, Leipzig, Germany..
    Tukiainen, Taru
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Willenborg, Christina
    DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Integrat & Expt Genom, Campus Lubeck, Lubeck, Germany.;Univ Heart Ctr Luebeck, Campus Lubeck, Lubeck, Germany..
    Won, Hong-Hee
    Sungkyunkwan Univ, Samsung Med Ctr, SAIHST, Seoul, South Korea..
    Zeng, Lingyao
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Zhang, Weihua
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England..
    Anand, Sonia S.
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Beutner, Frank
    LIFE Res Ctr Civilizat Dis, Leipzig, Germany.;Univ Leipzig, Heart Ctr Leipzig, Cardiol, Leipzig, Germany..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Clarke, Robert
    Univ Oxford, Nuffield Dept Populat Hlth, CTSU, Oxford, England..
    Dedoussis, George
    Harokopio Univ Athens, Athens, Greece..
    Do, Ron
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Ctr Stat Genet, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Zena & Michael A Weiner Cardiovasc Inst, New York, NY 10029 USA..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Eskola, Markku
    Heart Hosp, Dept Cariol, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland..
    Farrall, Martin
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Gauguier, Dominique
    INSERM, Ctr Rech Cordeliers, UMRS1138, Paris, France..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Granger, Christopher B.
    Duke Univ, Sch Med, Durham, NC USA..
    Hall, Alistair S.
    Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden..
    Hazen, Stanley L.
    Cleveland Clin, Cleveland, OH 44106 USA..
    Huang, Jie
    Boston VA Res Inst Inc, Boston, MA USA..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland..
    Kyriakou, Theodosios
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Laaksonen, Reijo
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland.;Zora Biosci, Espoo, Finland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Marouli, Eirini
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Nikus, Kjell
    Heart Hosp, Dept Cariol, Tampere, Finland.;Univ Tampere, Sch Med, Tampere, Finland..
    Pedersen, Nancy
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Rallidis, Loukianos
    Univ Gen Hosp Attikon, Dept Cardiol 2, Athens, Greece..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Shah, Svati H.
    Duke Univ, Sch Med, Durham, NC USA..
    Stewart, Alexandre F. R.
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Thompson, John R.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Zalloua, Pierre A.
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon.;Harvard Sch Publ Hlth, Boston, MA USA..
    Chambers, John C.
    Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England.;McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada.;Imperial Coll Healthcare NHS Trust, London, England..
    Collins, Rory
    Univ Oxford, Nuffield Dept Populat Hlth, CTSU, Oxford, England..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Iribarren, Carlos
    Kaiser Permanente, Div Res, Oakland, CA USA..
    Karhunen, Pekka J.
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Forens Med, Tampere, Finland..
    Kooner, Jaspal S.
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Cardiovasc Sci, Natl Heart & Lung Inst, London, England..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, Tampere, Finland..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.;Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    McPherson, Ruth
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Inst Mol & Cell Biol, Tartu, Estonia..
    Reilly, Muredach P.
    Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Ripatti, Samuli
    Kaiser Permanente, Div Res, Oakland, CA USA.;Univ Helsinki, Hjelt Inst, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Sanghera, Dharambir K.
    Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat, Oklahoma City, OK 73190 USA.;Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA.;Oklahoma Ctr Neurosci, Oklahoma City, OK USA..
    Thiery, Joachim
    LIFE Res Ctr Civilizat Dis, Leipzig, Germany.;Univ Hosp Leipzig, Fac Med, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany..
    Watkins, Hugh
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Wellcome Trust Sanger Inst, Cambridge, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Kathiresan, Sekar
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Schunkert, Heribert
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.;Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Erdmann, Jeanette
    DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany.;Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Integrat & Expt Genom, Campus Lubeck, Lubeck, Germany.;Univ Heart Ctr Luebeck, Campus Lubeck, Lubeck, Germany..
    Koenig, Inke R.
    Univ Lubeck, Univ Klinikum Schleswig Holstein, Inst Med Biometrie & Stat, Campus Lubeck, Lubeck, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Lubeck Kiel, Lubeck, Germany..
    No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 35278Article in journal (Refereed)
    Abstract [en]

    In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

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  • 295.
    Lorenz, Matthias W.
    et al.
    Goethe Univ, Dept Neurol, Frankfurt, Germany..
    Gao, Lu
    Univ Forvie Site, MRC, Biostat Unit, Inst Publ Hlth, Cambridge, England..
    Ziegelbauer, Kathrin
    Goethe Univ, Dept Neurol, Frankfurt, Germany..
    Norata, Giuseppe Danilo
    Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy.;Bassini Hosp, SISA Ctr Study Atherosclerosis, Cinisello Balsamo, Italy..
    Empana, Jean Philippe
    Univ Paris 05, Sorbonne Paris Cite, UMR, Paris Cardiovasc Res Ctr PARCC, Paris, France..
    Schmidtmann, Irene
    Univ Med Mainz, IMBEI, Mainz, Germany..
    Lin, Hung-Ju
    Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan..
    McLachlan, Stela
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Bokemark, Lena
    Gothenburg Univ, Sahlgrenska Acad, Dept Mol & Clin Med, Wallenberg Lab Cardiovasc Res,Inst Medicin, Gothenburg, Sweden..
    Ronkainen, Kimmo
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Amato, Mauro
    IRCCS, Ctr Cardiol Monzino, Milan, Italy..
    Schminke, Ulf
    Greifswald Univ Clin, Dept Neurol, Greifswald, Germany..
    Srinivasan, Sathanur R.
    Tulane Univ, Sch Publ Hlth & Trop Med, Ctr Cardiovasc Hlth, Dept Epidemiol,Biochem, New Orleans, LA USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Okazaki, Shuhei
    Osaka Univ, Grad Sch Med, Dept Neurol, Osaka, Japan..
    Stehouwer, Coen D. A.
    Maastricht Univ, Med Ctr, Dept Internal Med, Maastricht, Netherlands.;Maastricht Univ, Med Ctr, Cardiovasc Res Inst Maastricht CARIM, Maastricht, Netherlands..
    Willeit, Peter
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria.;Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England..
    Polak, Joseph F.
    Tufts Univ, Sch Med, Tufts Med Ctr, Boston, MA 02111 USA..
    Steinmetz, Helmuth
    Goethe Univ, Dept Neurol, Frankfurt, Germany..
    Sander, Dirk
    Benedictus Hosp Tutzing & Feldafing, Dept Neurol, Feldafing, Germany..
    Poppert, Holger
    Tech Univ Munich, Dept Neurol, Munich, Germany..
    Desvarieux, Moise
    Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA..
    Ikram, M. Arfan
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands..
    Johnsen, Stein Harald
    Uit, Dept Clin Med, Tromso, Norway.;Univ Hosp Northern Norway, Dept Neurol, Tromso, Norway..
    Staub, Daniel
    Univ Basel Hosp, Dept Angiol, Basel, Switzerland..
    Sirtori, Cesare R.
    Osped Niguarda Ca Granda, Ctr Dyslipidemias, Milan, Italy..
    Igiseder, Bernhard
    Parcelsus Med Univ, Salzburg, Austria.;Gemeinnutzige Salzburger Landeskliniken Betriebsg, Doppler Klin, Dept Geriatr Med, Salzburg, Austria..
    Beloqui, Oscar
    Univ Navarra Clin, Dept Internal Med, Navarra, Spain..
    Engstrom, Gunnar
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Friera, Alfonso
    Univ Autonoma Madrid, Hosp Univ La Princesa, Dept Radiol, Madrid, Spain..
    Rozza, Francesco
    Univ Naples Federico II, Sch Med, Naples, Italy..
    Xie, Wuxiang
    Capital Med Univ, Beijing Anzhen Hosp, Beijing Inst Heart Lung & Blood Vessel Dis, Dept Epidemiol, Beijing, Peoples R China..
    Parraga, Grace
    Western Univ, Roberts Res Inst, London, ON, Canada..
    Grigore, Liliana
    Bassini Hosp, Ctr Sisa Studio Aterosclerosi, Cinisello Balsamo, Italy..
    Plichart, Matthieu
    Hop Broca, AP HP, Paris, France..
    Blankenberg, Stefan
    Johannes Gutenberg Univ Mainz, Dept Med 2, Mainz, Germany.;Univ Hosp Hamburg Eppendorf, Dept Cardiol, Hamburg, Germany..
    Su, Ta-Chen
    Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan..
    Schmidt, Caroline
    Univ Gothenburg, Wallenberg Lab Cardiovasc Res, Gothenburg, Sweden..
    Tuomainen, Tomi-Pekka
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Veglia, Fabrizio
    IRCCS, Ctr Cardiol Monzino, Milan, Italy..
    Voelzke, Henry
    German Ctr Cardiovasc Res DZHK, Partner Site Greifswald, Greifswald, Germany.;Inst Community Med, SHIP Clin Epidemiol Res, Greifswald, Germany..
    Nijpels, Giel
    Vrije Univ Amsterdam, Dept Gen Practice, Medial Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands..
    Willeit, Johann
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA..
    Franco, Oscar H.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Uthoff, Heiko
    Univ Basel Hosp, Dept Angiol, Basel, Switzerland..
    Hedblad, Bo
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Suarez, Carmen
    Univ Autonoma Madrid, Hosp Univ La Princesa, Dept Internal Med, Madrid, Spain..
    Izzo, Raffaele
    Univ Naples Federico II, Sch Med, Naples, Italy..
    Zhao, Dong
    Capital Med Univ, Beijing Anzhen Hosp, Beijing Inst Heart Lung & Blood Vessel Dis, Dept Epidemiol, Beijing, Peoples R China..
    Wannarong, Thapat
    Western Univ, Stroke Prevent & Atherosclerosis Res Ctr, Roberts Res Inst, London, ON, Canada.;Mahidol Univ, Dept Internal Med, Fac Med, Siriraj Hosp, Bangkok, Thailand..
    Catapano, Alberico
    IRCSS Multimed, Milan, Italy.;Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy..
    Ducimetiere, Pierre
    Univ Paris Sud Xi, Le Kremlin Bicetre, France..
    Espinola-Klein, Christine
    Johannes Gutenberg Univ Mainz, Dept Med 2, Mainz, Germany..
    Chien, Kuo-Liong
    Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei, Taiwan..
    Price, Jackie F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Bergstrom, Goren
    Gothenburg Univ, Wallenberg Lab Cardiovasc Res, Sahlgrenska Acad, Gotheborg, Sweden..
    Kauhanen, Jussi
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Tremoli, Elena
    Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy.;IRCCS, Ctr Cardiol Monzino, Milan, Italy..
    Doerr, Marcus
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany..
    Berenson, Gerald
    Tulane Univ, Sch Med, Dept Med, Pediat,Biochem,Epidemiol, 1430 Tulane Ave, New Orleans, LA 70112 USA.;Sch Publ Hlth & Trop Med, New Orleans, LA USA..
    Kitagawa, Kazuo
    Tokyo Womens Med Univ, Dept Neurol, Tokyo, Japan..
    Dekker, Jacqueline M.
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, Dept Epidemiol & Biostat, Amsterdam, Netherlands..
    Kiechl, Stefan
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Sitzer, Matthias
    Klinikum Herford, Dept Neuol, Herford, Germany..
    Bickel, Horst
    Tech Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany..
    Rundek, Tatjana
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA..
    Hofman, Albert
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Mathiesen, Ellisiv B.
    Uit, Dept Clin Med, Tromso, Norway..
    Castelnuovo, Samuela
    Osped Niguarda Ca Granda, Ctr Dyslipidemias, Milan, Italy..
    Landecho, Manuel F.
    Univ Navarra Clin, Dept Internal Med, Navarra, Spain..
    Rosvall, Maria
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Gabriel, Rafael
    Inst Salud Carlos III, Escuela Natl Sanidad, Madrid, Spain..
    de Luca, Nicola
    Univ Naples Federico II, Sch Med, Naples, Italy..
    Liu, Jing
    Capital Med Univ, Beijing Anzhen Hosp, Beijing Inst Heart Lung & Blood Vessel Dis, Dept Epidemiol, Beijing, Peoples R China..
    Baldassarre, Damiano
    Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy.;IRCCS, Ctr Cardiol Monzino, Milan, Italy..
    Kavousi, Maryam
    Erasmus MC, Dept Epidemiol & Biostat, Rotterdam, Netherlands..
    de Groot, Eric
    Imagelabonline & Cardiovasc, Eindhoven, Netherlands.;Imagelabonline & Cardiovasc, Lunteren, Netherlands.;Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands..
    Bots, Michiel L.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Yanez, David N.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Thompson, Simon G.
    Univ Cambridge, Sch Clin Med, Dept Publ Hlth & Primary Care, Cambridge, England..
    Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 4, article id e0191172Article in journal (Refereed)
    Abstract [en]

    Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.

    Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.

    Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

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  • 296.
    Lorenz, Matthias W.
    et al.
    Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany..
    Price, Jackie F.
    Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland..
    Robertson, Christine
    Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland..
    Bots, Michiel L.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Polak, Joseph F.
    Tufts Univ, Sch Med, Tufts Med Ctr, Boston, MA 02111 USA..
    Poppert, Holger
    Tech Univ Munich, Univ Hosp, Dept Neurol, D-80290 Munich, Germany..
    Kavousi, Maryam
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Doerr, Marcus
    Greifswald Univ Clin, Dept Internal Med Cardiol B, Greifswald, Germany..
    Stensland, Eva
    Univ Tromso, Dept Clin Med, Tromso, Norway..
    Ducimetiere, Pierre
    Univ Paris 11, Paris, France..
    Ronkainen, Kimmo
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Kiechl, Stefan
    Med Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria..
    Sitzer, Matthias
    Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany.;Klinikum Herford, Dept Neurol, Herford, Germany..
    Rundek, Tatjana
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Liu, Jing
    Inst Heart Lung & Blood Vessel Dis, Dept Epidemiol, Beijing, Peoples R China..
    Bergstrom, Goran
    Univ Gothenburg, Wallenberg Lab Cardiovasc Res, Gothenburg, Sweden..
    Grigore, Liliana
    Bassini Hosp, SISA Ctr Study Atherosclerosis, Cinisello Balsamo, Italy.;IRCCS MultiMed, Milan, Italy..
    Bokemark, Lena
    Univ Gothenburg, Wallenberg Lab Cardiovasc Res, Gothenburg, Sweden..
    Friera, Alfonsa
    Univ Autonoma Madrid, Hosp Univ la Princesa, Dept Radiol, Madrid, Spain..
    Yanez, David
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Bickel, Horst
    Tech Univ Munich, Univ Hosp, Dept Psychiat, D-80290 Munich, Germany..
    Ikram, M. Arfan
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Voelzke, Henry
    Ernst Moritz Arndt Univ Greifswald, SHIP Clin Epidemiol Res, Inst Community Med, Greifswald, Germany.;German Ctr Cardiovasc Res, Greifswald, Germany..
    Johnsen, Stein Harald
    Univ Tromso, Dept Clin Med, Tromso, Norway.;Univ Hosp Northern Norway, Dept Neurol & Neurophysiol, Tromso, Norway..
    Empana, Jean Philippe
    INSERM U970, Paris, France..
    Tuomainen, Tomi-Pekka
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Willeit, Peter
    Med Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England..
    Steinmetz, Helmuth
    Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany..
    Desvarieux, Moise
    Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.;Ecole Hautes Etud Sante Publ, Paris, France.;INSERM U738, Paris, France..
    Xie, Wuxiang
    Inst Heart Lung & Blood Vessel Dis, Dept Epidemiol, Beijing, Peoples R China..
    Schmidt, Caroline
    Univ Gothenburg, Wallenberg Lab Cardiovasc Res, Gothenburg, Sweden..
    Norata, Giuseppe D.
    Bassini Hosp, SISA Ctr Study Atherosclerosis, Cinisello Balsamo, Italy.;Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy..
    Suarez, Carmen
    Univ Autonoma Madrid, Hosp Univ la Princesa, Dept Internal Med, Madrid, Spain..
    Sander, Dirk
    Tech Univ Munich, Univ Hosp, Dept Neurol, D-80290 Munich, Germany.;Benedictus Hosp Tutzing & Feldafing, Dept Neurol, Feldafing, Germany..
    Hofman, Albert
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Schminke, Ulf
    Greifswald Univ Clin, Dept Neurol, Greifswald, Germany..
    Mathiesen, Ellisiv
    Univ Tromso, Dept Clin Med, Tromso, Norway.;Univ Hosp Northern Norway, Dept Neurol & Neurophysiol, Tromso, Norway..
    Plichart, Matthieu
    INSERM U970, Paris, France.;Broca Hosp, Gerontol Dept, Paris, France..
    Kauhanen, Jussi
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Willeit, Johann
    Med Univ Innsbruck, Dept Neurol, A-6020 Innsbruck, Austria..
    Sacco, Ralph L.
    Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA..
    McLachlan, Stela
    Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland..
    Zhao, Dong
    Inst Heart Lung & Blood Vessel Dis, Dept Epidemiol, Beijing, Peoples R China..
    Fagerberg, Bjorn
    Univ Gothenburg, Wallenberg Lab Cardiovasc Res, Gothenburg, Sweden..
    Catapano, Alberico L.
    IRCCS MultiMed, Milan, Italy.;Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy..
    Gabriel, Rafael
    Univ Autonoma Madrid, Hosp Univ La Paz, Inst Invest IdiPAZ, Madrid, Spain..
    Franco, Oscar H.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Buelbuel, Alpaslan
    Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany..
    Scheckenbach, Frank
    Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany..
    Pflug, Anja
    Goethe Univ Frankfurt, Dept Neurol, D-60054 Frankfurt, Germany..
    Gao, Lu
    Inst Publ Hlth, MRC, Biostat Unit, Cambridge, England..
    Thompson, Simon G.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England..
    Carotid Intima-Media Thickness Progression and Risk of Vascular Events in People With Diabetes: Results From the PROG-IMT Collaboration2015In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 38, no 10, p. 1921-1929Article in journal (Refereed)
    Abstract [en]

    OBJECTIVECarotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes.RESEARCH DESIGN AND METHODSIn a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33-92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis.RESULTSAverage mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12-1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between -0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91-1.08).CONCLUSIONSDespite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.

  • 297. 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Omenaas, Ernst
    Joshi, Peter K
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wild, Sarah H
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, 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 University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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 capacity2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, p. 669-677Article in journal (Refereed)
    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.

  • 298. Lovdahl, S.
    et al.
    Henriksson, Karin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Baghaei, F.
    Holmstrom, M.
    Berntorp, E.
    Astermark, J.
    A longitudinal study of family structure in Swedish persons with haemophilia2014In: Haemophilia, ISSN 1351-8216, E-ISSN 1365-2516, Vol. 20, no 4, p. 493-499Article in journal (Refereed)
    Abstract [en]

    Haemophilia is an X-linked inherited rare bleeding disorder affecting mainly men. The treatment consists of replacement therapy that has been associated with severe side effects, such as blood transmitted viral infections, but has markedly improved over the last decades. The aim of this study was to study family structure over time among Swedish persons with haemophilia (PWH), focusing on children, siblings and marital status. PWH A or B were identified from the haemophilia centres and the national Patient Registry. Each PWH was compared to five age- and gender-matched controls. The national Multi-Generation Registry was used to identify children and siblings. A total of 1365 children with a father suffering from haemophilia A or B and 1938 siblings of the PWH were identified. Having one or more children was significantly less common (P=0.003) for PWH than for controls. Significantly lower rates of having a child were also found for the subgroups of persons suffering from severe haemophilia and those infected with HIV (P<0.001). A higher proportion of PWH, with or without HIV and/or viral hepatitis had siblings compared to the controls (P<0.001). However, the mean number of siblings was significantly lower for persons with severe haemophilia (P=0.001). The number of marriages and divorces did not differ between PWH and controls. Our data indicate a negative impact of HIV and viral hepatitis on family structure for PWH despite the relatively good access to treatment in Sweden over the last few decades. This was particularly true for those with a severe form of haemophilia.

  • 299.
    Lovdahl, Susanna
    et al.
    Lund Univ, Dept Translat Med, Clin Coagulat Res Unit, Malmo, Sweden.
    Henriksson, Karin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. AstraZeneca, Dept Epidemiol, R&D, Molndal, Sweden.
    Baghaei, Fariba
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med Hematol & Coagulat Disorders, Coagulat Ctr, Gothenburg, Sweden.
    Holmstrom, Margareta
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Coagulat Unit, Stockholm, Sweden.
    Berntorp, Erik
    Lund Univ, Dept Translat Med, Clin Coagulat Res Unit, Malmo, Sweden.
    Astermark, Jan
    Lund Univ, Dept Translat Med, Clin Coagulat Res Unit, Malmo, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Malmo, Sweden.
    Hypertension and cardiovascular diseases in Swedish persons with haemophilia - A longitudinal registry study2019In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 181, p. 106-111Article in journal (Refereed)
    Abstract [en]

    Introduction: Data on the prevalence of hypertension and cardiovascular diseases (CVD) among persons with haemophilia (PWH) vary. Sweden has a long tradition of maintaining population-based data registries, and there is extensive follow-up of haemophilia patients due to the use of prophylaxis over decades. We evaluated the prevalence of these diseases among Swedish PWH compared to matched controls using a longitudinal study design.

    Methods: Data were obtained from the National Patient Registry and linked to records of persons with haemophilia enrolled in the haemophilia centres. For each subject, five gender and age matched controls were identified.

    Results: We identified 193 (19.7%) diagnoses of hypertension in PWH born in 1978 or earlier over >= 30 years compared with 550 (11.2%) among controls. The median ages and interquartile ranges were 60.0 (42.8, 69.9) and 57.2 (42.6, 70.6) years. The hazard rate (HR) for hypertension, PWH vs. controls, was 2.1, 95% CI: [1.8; 2.5], p < 0.001. The findings were similar in subgroup analyses of patients with non-severe and severe haemophilia with or without HIV and/or viral hepatitis. Angina pectoris was diagnosed in 69 (4.8%) of patients censored at age 75 compared with 311 (4.3%) in controls, and myocardial ischemia in 84 (5.9%) compared with 442 (6.2%). As a cause of death, the HR for myocardial ischemia, comparing PWH and controls, was 0.58, 95% CI: [0.42, 0.80], p = 0.001.

    Conclusion: Our data support an increased prevalence of hypertension among persons with haemophilia. The prevalence of CVD seems to be similar to that of controls, but with lower mortality.

  • 300. Lovdahl, Susanna
    et al.
    Henriksson, Karin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Baghaei, Fariba
    Holmstrom, Margareta
    Berntorp, Erik
    Astermark, Jan
    Malignant Diseases in Swedish Person with Heamophilia-A Longitudinal Registry Study2014In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 23, no S1, p. 209-210Article in journal (Other academic)
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