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  • 1. Abarca-Gómez, L.
    et al.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lytsy, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Yngve, Agneta
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Food, Nutrition and Dietetics.
    Ezzati, M
    Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults.2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10113, p. 2627-2642Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults.

    METHODS: We pooled 2416 population-based studies with measurements of height and weight on 128·9 million participants aged 5 years and older, including 31·5 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity).

    FINDINGS: Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0·01 kg/m(2) per decade; 95% credible interval -0·42 to 0·39, posterior probability [PP] of the observed decrease being a true decrease=0·5098) in eastern Europe to an increase of 1·00 kg/m(2) per decade (0·69-1·35, PP>0·9999) in central Latin America and an increase of 0·95 kg/m(2) per decade (0·64-1·25, PP>0·9999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0·09 kg/m(2) per decade (-0·33 to 0·49, PP=0·6926) in eastern Europe to an increase of 0·77 kg/m(2) per decade (0·50-1·06, PP>0·9999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0·7% (0·4-1·2) in 1975 to 5·6% (4·8-6·5) in 2016 in girls, and from 0·9% (0·5-1·3) in 1975 to 7·8% (6·7-9·1) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9·2% (6·0-12·9) in 1975 to 8·4% (6·8-10·1) in 2016 in girls and from 14·8% (10·4-19·5) in 1975 to 12·4% (10·3-14·5) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22·7% (16·7-29·6) among girls and 30·7% (23·5-38·0) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese.

    INTERPRETATION: The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults.

  • 2. Abrahamsson, Christina
    et al.
    Ahlund, Catherine
    Nordlander, Margareta
    Lind, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    A method for heart rate-corrected estimation of baroreflex sensitivity.2003In: J Hypertens, ISSN 0263-6352, Vol. 21, no 11, p. 2133-40Article in journal (Refereed)
  • 3.
    Ahlström, Tommy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rudberg, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women2009In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 71, no 5, p. 673-678Article in journal (Refereed)
    Abstract [en]

    CONTEXT: In recent years, an association has been noted between several abnormalities that characterize the metabolic syndrome (MetS) and primary hyperparathyroidism (pHPT). These abnormalities include dyslipidaemia, obesity, insulin resistance and hypertension. The correlations between plasma calcium, parathyroid hormone (PTH) and the variables in the MetS in a normal population are still unclear.

    OBJECTIVE: To describe correlations between plasma calcium and PTH and the various abnormalities present in the MetS in a healthy population.

    DESIGN: We studied 1016 healthy individuals from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) population of 70 years old, by means of plasma analyses of calcium, PTH, creatinine, lipids, insulin and glucose, as well as by standardized blood pressure measurements. Further, body mass index (BMI) and waist circumference were determined.

    RESULTS: The more National Cholesterol Education Program (NCEP) criteria for the MetS that were met, the higher the s-PTH and albumin-corrected s-calcium. Further, positive correlations between plasma calcium and BMI (P = 0.0003), waist circumference (P = 0.0009) and insulin resistance (P = 0.079) were found. PTH and BMI (P < 0.0001), waist circumference (P < 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated.

    CONCLUSIONS: We conclude that PTH correlates with several of the metabolic factors included in the MetS within a normocalcaemic population. In addition, individuals with mild pHPT present significantly more NCEP criteria for MetS. We postulate that increased levels of PTH in pHPT may be associated with the increased cardiovascular morbidity and mortality seen in pHPT.

  • 4. Ahlund, Catherine
    et al.
    Pettersson, Knut
    Lind, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Influence of different types of stressors on the waveform of the peripheral arterial pulse in humans.2003In: Blood Press, ISSN 0803-7051, Vol. 12, no 5-6, p. 291-7Article in journal (Refereed)
  • 5.
    Andersen, Kasper
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Muscle Morphology And Risk Of Cardiovascular Disease2010In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 28, p. E353-E353Article in journal (Other academic)
  • 6.
    Andersen, Kasper
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    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.
    Skeletal muscle morphology and risk of cardiovascular disease in elderly men2015In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 22, no 2, p. 231-239Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    While it is well known that physical inactivity is a major risk factor for cardiovascular disease, there is still a search for the mechanisms by which exercise exerts its positive effect. Skeletal muscle fibre type can be affected to some extent by exercise, and different fibre types possess different anti-inflammatory and glucometabolic properties that may influence cardiovascular disease risk.

    DESIGN:

    Population-based cohort study.

    METHODS:

    We investigated relations of skeletal muscle morphology to risk of cardiovascular events in a sample of 466 71-year-old men without cardiovascular disease, of which 295 were physically active (strenuous physical activity at least 3 h/week).

    RESULTS:

    During a median of 13.1 years of follow up, 173 major cardiovascular events occurred. Among physically active men, 10% higher proportion of type-I (slow-twitch oxidative) fibres was associated with a hazard ratio (HR) of 0.84 (95% confidence interval 0.74-0.95) for cardiovascular events, and 10% higher proportion of type-IIx (fast-twitch glycolytic) fibres was associated with a HR of 1.24 (1.06-1.45), adjusting for age. Similar results were observed in several sets of multivariable-adjusted models. No association of muscle fibre type with risk of cardiovascular events was observed among physically inactive men.

    CONCLUSIONS:

    Higher skeletal muscle proportion of type-I fibres was associated with lower risk of cardiovascular events and a higher proportion of type-IIx fibres was associated with higher risk of cardiovascular events. These relations were only observed in physically active men. Skeletal muscle fibre composition may be a mediator of the protective effects of exercise against cardiovascular disease.

  • 7.
    Andersson, Helén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lind, P. Monica
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Eva, Brittebo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Experimental studies of bisphenol A in cardiovascular cells and tissues: effects on genes that regulate angiogenesis and vascular tone2012In:  , 2012Conference paper (Refereed)
  • 8.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cyclooxygenase inhibition improves endothelium-dependent vasodilatation in patients with chronic renal failure2002In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 17, no 12, p. 2159-2163Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some studies have demonstrated beneficial effects of L-arginine as a substrate for nitric oxide synthesis, and diclofenac as an inhibitor of cyclooxygenase (COX)-derived vasoconstrictive agents on vascular responses in humans during several pathological conditions. The aim of the present study was to investigate the acute effects of L-arginine and diclofenac on endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIDV) in patients with chronic renal failure (CRF).

    METHODS: Effects of L-arginine and diclofenac on EDV and EIDV were measured in 15 patients with CRF and in 15 healthy controls by means of forearm blood flow measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (2 and 4 micro g/min evaluating EDV) and sodium nitroprusside (5 and 10 micro g/min evaluating EIDV).

    RESULTS: L-Arginine infusion increased methacholine-induced vasodilatation both in patients with CRF and healthy controls. Diclofenac infusion increased methacholine-induced vasodilatation only in patients with CRF. There was no significant change in nitroprusside-induced vasodilatation after L-arginine and diclofenac infusions both in patients with CRF and healthy controls.

    CONCLUSIONS: These results suggest that COX inhibition reduces the levels of a prostanoid-derived vasoconstrictive agent contributing to the impaired EDV in patients with CRF, while in this age group L-arginine improves EDV regardless of renal function.

  • 9.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Impaired endothelium-dependent vasodilatation in renal failure in humans2001In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 16, no 2, p. 302-306Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The main causes of death in patients with chronic renal failure (CRF) are cardiovascular complications. The aim of the present study was to compare endothelium-dependent vasodilatation (EDV) in patients with chronic renal failure with a control population controlling for hypertension, diabetes mellitus and hypercholesterolaemia.

    METHODS: Fifty-six patients with moderate CRF (mean creatinine clearance 29.4 ml/min/1.73 m(2)) underwent evaluation of EDV and endothelium-independent vasodilatation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (Mch, 2 and 4 microg/min evaluating EDV) and sodium nitroprusside (SNP, 5 and 10 microg/min evaluating EIDV). Fifty-six control subjects without renal impairment underwent the same investigation.

    RESULTS: Infusion of Mch increased FBF significantly less in patients with renal failure than in controls (198 vs 374%, P<0.001), whereas no significant difference was seen regarding the vasodilatation induced by SNP (278 vs 269%). The differences in EDV between the groups were still significant after controlling for hypertension, blood glucose, and serum cholesterol in multiple regression analysis (P<0.001). EDV was related to serum creatinine (r=-0.37, P<0.01), creatinine clearance (r=0.45, P<0.005) and to serum triglyceride levels (r=-0.29, P<0.005) in the CRF group.

    CONCLUSIONS: Patients with moderate CRF have an impaired EDV even after correction for traditional cardiovascular risk factors and this impairment is related to the degree of renal failure.

  • 10.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Erythropoietin impairs endothelial vasodilatory function in patients with renal anemia and in healthy subjects2006In: Nephron. Clinical practice, ISSN 1660-8151, E-ISSN 2235-3186, Vol. 102, no 1, p. c30-c34Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The mechanisms underlying the aggravation or development of hypertension frequently seen during treatment of renal anemia with epoetins are not fully elucidated. The aim of the present study was to investigate the effects of epoetin alfa on endothelial vasodilatory function in patients with renal anemia and in healthy subjects. Methods: Eighteen preuremic patients with anemia (GFR 23.4 ± 11 SD ml/min, Hb 101 ± 8 g/l) and 10 healthy subjects underwent evaluation of endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV). These investigations were performed before and 30 min after an intravenous injection of epoetin alfa (10,000 IU). Ten healthy subjects underwent the same procedure with the exception that saline were given instead of epoetin. The patients were treated with epoetin alfa subcutaneously for 12-19 weeks and revaluated when Hb exceeded 120 g/l. Results: EDV was attenuated after the epoetin injection in both renal patients and healthy subjects. This impairment persisted after anemia had been treated. EDIV and blood pressure remained constant. Saline had no effect on the variables measured. Conclusion: Our results indicate that epoetin alfa impairs endothelial function in renal patients and healthy subjects which may have an impact on vascular complications.

  • 11.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zilmer, Mihkel
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hulthe, Johannes
    Fellström, Bengt
    Endothelial function, CRP and oxidative stress in chronic kidney disease2005In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 18, no 6, p. 721-726Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic kidney disease (CKD) is associated with increased morbidity and mortality in cardiovascular disease (CVD). Apart from traditional risk factors, chronic inflammation, oxidative stress, malnutrition and endothelial dysfunction are important in CVD development in renal patients. Our aim was to investigate the relationship between high sensitivity C-reactive protein (CRP), endothelium dependent vasodilation (EDV) and oxidative stress markers in patients with CKD K/DOQI stage 3-5.

    METHODS: Measurements of CRP, conjugated dienes (CD), lipid hydroperoxide (LOOH), oxidized low density lipoprotein,glutathione and albumin were performed in 44 consecutive patients with CKD stage 3-5. EDV was measured by methacholine infusion in the brachial artery and venous occlusion plethysmography.

    RESULTS: Patients with high CRP had significantly lower glomerular filtration rates and albumin, but increased LOOH and CD. In multiple regression analysis, only LOOH and CD remained significant. Patients with poor EDV had increased urea and lower glutathione (GSH). In multiple regression analysis, GSH and urea were independently related to EDV. No correlation was found between CRP and endothelial function.

    CONCLUSION: CRP was related to lipid peroxidation, while endothelial function was related to intracellular oxidative stress in patients with CKD. CRP and EDV were unrelated to each other. Therefore, CRP and endothelial function could provide complementary prognostic information regarding future cardiovascular disorders in renal patients.

  • 12.
    Annuk, Margus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zilmer, Mikhel
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Linde, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oxidative stress and endothelial function in chronic renal failure2001In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 12, no 12, p. 2747-2752Article in journal (Other academic)
    Abstract [en]

    This study aimed to investigate the relationship between oxidative stress and endothelium-dependent vasodilation in patients with chronic renal failure (CRF). Thirty-seven patients with CRF underwent evaluation of endothelium-dependent vasodilation and endothelium-independent vasodilation by means of forearm blood flow measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (evaluating endothelium-dependent vasodilation) and sodium nitroprusside (evaluating endothelium-independent vasodilation). Lag phase of lipoprotein fraction to oxidation, total antioxidative activity, diene conjugates, thiobarbituric acid reactive substances, lipid hydroperoxide, reduced glutathione (GSH), oxidized GSH (GSSG), and the GSH redox ratio (GSSG/GSH) were all measured as markers of oxidative stress. Two groups of healthy subjects (61 and 37 subjects, respectively) were used as controls. In one group, oxidative stress markers were measured, whereas endothelium-dependent vasodilation and endothelium-independent vasodilation were assessed in the other group. Compared with controls, the patients with renal insufficiency had an impaired endothelium-dependent vasodilation, a shorter lag phase of lipoprotein fraction, and higher levels of diene conjugates, lipid hydroperoxide, and GSSG levels. The GSSG/GSH ratio was lower in patients with CRF. Endothelium-dependent vasodilation was positively correlated with total antioxidative activity (r = 0.41, P = 0.016), GSH (r = 0.44, P < 0.0098), and lag phase of LDL (r = 0.35, P = 0.036) and negatively correlated with GSSG (r = -0.40, P < 0.018), GSSG/GSH (r = -0.47, P = 0.0057), and diene conjugates (r = -0.53 P < 0.0015) in patients with CRF. These results show that an impaired endothelium vasodilation function and oxidative stress are related to each other in patients with CRF.

  • 13.
    Arefalk, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hambraeus, Kristina
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    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.
    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.
    Discontinuation of Smokeless Tobacco and Mortality Risk After Myocardial Infarction2014In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 130, no 4, p. 325-323Article in journal (Refereed)
    Abstract [en]

    Background-Given the indications of increased risk for fatal myocardial infarction (MI) in people who use snus, a moist smokeless tobacco product, we hypothesized that discontinuation of snus use after an MI would reduce mortality risk. Methods and Results-All patients who were admitted to coronary care units for an MI in Sweden between 2005 and 2009 and were <75 years of age underwent a structured examination 2 months after discharge (the baseline of the present study). We investigated the risk of mortality in post-MI snus quitters (n=675) relative to post-MI continuing snus users (n=1799) using Cox proportional hazards analyses. During follow-up (mean 2.1 years), 83 participants died. The mortality rate was 9.7 (95% confidence interval, 5.7-16.3) per 1000 person-years at risk in post-MI snus quitters and 18.7 (14.8-23.6) per 1000 person-years at risk in post-MI continuing snus users. After adjustment for age and sex, post-MI snus quitters had half the mortality risk of post-MI continuing snus users (hazard ratio, 0.51; 95% confidence interval, 0.29-0.91). In a multivariable-adjusted model, the hazard ratio was 0.57 (95% confidence interval, 0.32-1.02). The corresponding estimate for people who quit smoking after MI versus post-MI continuing smokers was 0.54 (95% confidence interval, 0.42-0.69). Conclusions-In this study, discontinuation of snus use after an MI was associated with a nearly halved mortality risk, similar to the benefit associated with smoking cessation. These observations suggest that the use of snus after MI should be discouraged.

  • 14.
    Arefalk, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hambraeus, Kristina
    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, Center for Clinical Research Dalarna.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lindahl, Bertil
    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.
    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.
    Response to Letter Regarding Article, "Discontinuation of Smokeless Tobacco and Mortality Risk After Myocardial Infarction"2015In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 131, no 17, p. E423-E423Article in journal (Refereed)
  • 15.
    Arefalk, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hergens, M. P.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ye, W.
    Nyrén, O.
    Lambe, M.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Smokeless Tobacco (Snus) And Risk Of Heart Failure In Two Swedish Cohorts2010In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 28, p. E48-E49Article in journal (Other academic)
  • 16.
    Arefalk, Gabriel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Hergens, Maria-Pia
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ye, Weimin
    Nyrén, Olof
    Lambe, Mats
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Smokeless Tobacco (Snus) and Risk of Heart Failure: Results from Two Swedish Cohorts2012In: European Journal of Cardiovascular Prevention & Rehabilitation, ISSN 1741-8267, E-ISSN 1741-8275, Vol. 19, no 5, p. 1120-1127Article in journal (Refereed)
    Abstract [en]

    Background:

    Oral moist snuff (snus) is discussed as a safer alternative to smoking, and its use is increasing. Based on its documented effect on blood pressure, we hypothesized that use of snus increases the risk of heart failure.

    Design:

    Two independent Swedish prospective cohorts; the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based sample of 1076 elderly men, and the Construction Workers Cohort (CWC), a sample of 118,425 never-smoking male construction workers.

    Methods:

    Cox proportional hazards models were used to investigate possible associations of snus use with risk of a first hospitalization for heart failure.

    Results:

    In ULSAM, 95 men were hospitalized for heart failure, during a median follow up of 8.9 years. In a model adjusted for established risk factors including past and present smoking exposure, current snus use was associated with a higher risk of heart failure [hazard ratio (HR) 2.08, 95% confidence interval (CI) 1.03-4.22] relative to non-use. Snus use was particularly associated with risk of non-ischaemic heart failure (HR 2.55, 95% CI 1.12-5.82). In CWC, 545 men were hospitalized for heart failure, during a median follow up of 18 years. In multivariable-adjusted models, current snus use was moderately associated with a higher risk of heart failure (HR 1.28, 95% CI 1.00-1.64) and non-ischaemic heart failure (HR 1.28, 95% CI 0.97-1.68) relative to never tobacco use.

    Conclusion:

    Data from two independent cohorts suggest that use of snus may be associated with a higher risk of heart failure.

  • 17. Arking, Dan E
    et al.
    Pulit, Sara L
    Crotti, Lia
    van der Harst, Pim
    Munroe, Patricia B
    Koopmann, Tamara T
    Sotoodehnia, Nona
    Rossin, Elizabeth J
    Morley, Michael
    Wang, Xinchen
    Johnson, Andrew D
    Lundby, Alicia
    Gudbjartsson, Daníel F
    Noseworthy, Peter A
    Eijgelsheim, Mark
    Bradford, Yuki
    Tarasov, Kirill V
    Dörr, Marcus
    Müller-Nurasyid, Martina
    Lahtinen, Annukka M
    Nolte, Ilja M
    Smith, Albert Vernon
    Bis, Joshua C
    Isaacs, Aaron
    Newhouse, Stephen J
    Evans, Daniel S
    Post, Wendy S
    Waggott, Daryl
    Lyytikäinen, Leo-Pekka
    Hicks, Andrew A
    Eisele, Lewin
    Ellinghaus, David
    Hayward, Caroline
    Navarro, Pau
    Ulivi, Sheila
    Tanaka, Toshiko
    Tester, David J
    Chatel, Stéphanie
    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.
    Kumari, Meena
    Morris, Richard W
    Naluai, Asa T
    Padmanabhan, Sandosh
    Kluttig, Alexander
    Strohmer, Bernhard
    Panayiotou, Andrie G
    Torres, Maria
    Knoflach, Michael
    Hubacek, Jaroslav A
    Slowikowski, Kamil
    Raychaudhuri, Soumya
    Kumar, Runjun D
    Harris, Tamara B
    Launer, Lenore J
    Shuldiner, Alan R
    Alonso, Alvaro
    Bader, Joel S
    Ehret, Georg
    Huang, Hailiang
    Kao, W H Linda
    Strait, James B
    Macfarlane, Peter W
    Brown, Morris
    Caulfield, Mark J
    Samani, Nilesh J
    Kronenberg, Florian
    Willeit, Johann
    Smith, J Gustav
    Greiser, Karin H
    Meyer Zu Schwabedissen, Henriette
    Werdan, Karl
    Carella, Massimo
    Zelante, Leopoldo
    Heckbert, Susan R
    Psaty, Bruce M
    Rotter, Jerome I
    Kolcic, Ivana
    Polašek, Ozren
    Wright, Alan F
    Griffin, Maura
    Daly, Mark J
    Arnar, David O
    Hólm, Hilma
    Thorsteinsdottir, Unnur
    Denny, Joshua C
    Roden, Dan M
    Zuvich, Rebecca L
    Emilsson, Valur
    Plump, Andrew S
    Larson, Martin G
    O'Donnell, Christopher J
    Yin, Xiaoyan
    Bobbo, Marco
    D'Adamo, Adamo P
    Iorio, Annamaria
    Sinagra, Gianfranco
    Carracedo, Angel
    Cummings, Steven R
    Nalls, Michael A
    Jula, Antti
    Kontula, Kimmo K
    Marjamaa, Annukka
    Oikarinen, Lasse
    Perola, Markus
    Porthan, Kimmo
    Erbel, Raimund
    Hoffmann, Per
    Jöckel, Karl-Heinz
    Kälsch, Hagen
    Nöthen, Markus M
    den Hoed, Marcel
    Loos, Ruth J F
    Thelle, Dag S
    Gieger, Christian
    Meitinger, Thomas
    Perz, Siegfried
    Peters, Annette
    Prucha, Hanna
    Sinner, Moritz F
    Waldenberger, Melanie
    de Boer, Rudolf A
    Franke, Lude
    van der Vleuten, Pieter A
    Beckmann, Britt Maria
    Martens, Eimo
    Bardai, Abdennasser
    Hofman, Nynke
    Wilde, Arthur A M
    Behr, Elijah R
    Dalageorgou, Chrysoula
    Giudicessi, John R
    Medeiros-Domingo, Argelia
    Barc, Julien
    Kyndt, Florence
    Probst, Vincent
    Ghidoni, Alice
    Insolia, Roberto
    Hamilton, Robert M
    Scherer, Stephen W
    Brandimarto, Jeffrey
    Margulies, Kenneth
    Moravec, Christine E
    Greco M, Fabiola Del
    Fuchsberger, Christian
    O'Connell, Jeffrey R
    Lee, Wai K
    Watt, Graham C M
    Campbell, Harry
    Wild, Sarah H
    El Mokhtari, Nour E
    Frey, Norbert
    Asselbergs, Folkert W
    Mateo Leach, Irene
    Navis, Gerjan
    van den Berg, Maarten P
    van Veldhuisen, Dirk J
    Kellis, Manolis
    Krijthe, Bouwe P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Franco, Oscar H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hofman, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kors, Jan A
    Uitterlinden, André G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Witteman, Jacqueline C M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kedenko, Lyudmyla
    Lamina, Claudia
    Oostra, Ben A
    Abecasis, Gonçalo R
    Lakatta, Edward G
    Mulas, Antonella
    Orrú, Marco
    Schlessinger, David
    Uda, Manuela
    Markus, Marcello R P
    Völker, Uwe
    Snieder, Harold
    Spector, Timothy D
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sundström, Johan
    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.
    Kivimaki, Mika
    Kähönen, Mika
    Mononen, Nina
    Raitakari, Olli T
    Viikari, Jorma S
    Adamkova, Vera
    Kiechl, Stefan
    Brion, Maria
    Nicolaides, Andrew N
    Paulweber, Bernhard
    Haerting, Johannes
    Dominiczak, Anna F
    Nyberg, Fredrik
    Whincup, Peter H
    Hingorani, Aroon D
    Schott, Jean-Jacques
    Bezzina, Connie R
    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.
    Ferrucci, Luigi
    Gasparini, Paolo
    Wilson, James F
    Rudan, Igor
    Franke, Andre
    Mühleisen, Thomas W
    Pramstaller, Peter P
    Lehtimäki, Terho J
    Paterson, Andrew D
    Parsa, Afshin
    Liu, Yongmei
    van Duijn, Cornelia M
    Siscovick, David S
    Gudnason, Vilmundur
    Jamshidi, Yalda
    Salomaa, Veikko
    Felix, Stephan B
    Sanna, Serena
    Ritchie, Marylyn D
    Stricker, Bruno H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stefansson, Kari
    Boyer, Laurie A
    Cappola, Thomas P
    Olsen, Jesper V
    Lage, Kasper
    Schwartz, Peter J
    Kääb, Stefan
    Chakravarti, Aravinda
    Ackerman, Michael J
    Pfeufer, Arne
    de Bakker, Paul I W
    Newton-Cheh, Christopher
    Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 8, p. 826-836Article in journal (Refereed)
    Abstract [en]

    The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

  • 18. Arnlov, Johan
    et al.
    Carlsson, Axel C.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Larsson, Tobias E.
    Serum FGF23 and Risk of Cardiovascular Events in Relation to Mineral Metabolism and Cardiovascular Pathology2013In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 8, no 5, p. 781-786Article in journal (Refereed)
    Abstract [en]

    Background and objectives Circulating fibroblast growth factor-23 is associated with adverse cardiovascular outcomes in CKD and non-CKD individuals, but the underlying mechanism remains unclear. This study tested whether this association is independent of mineral metabolism and indices of subclinical cardiovascular pathology. Design, setting, participants, & measurements The prospective association between fibroblast growth factor-23 and major cardiovascular events (a composite of hospital-treated myocardial infarction, hospital-treated stroke, or all-cause mortality) was investigated in the community-based Prospective Investigation of the Vasculature in Uppsala Seniors (n=973; mean age=70 years, 50% women) using multivariate logistic regression. Subjects were recruited between January of 2001 and June of 2004. Results During follow-up (median=5.1 years), 112 participants suffered a major cardiovascular event. In logistic regression models adjusted for age, sex, and estimated GFR, higher fibroblast growth factor-23 was associated with increased risk for major cardiovascular events (odds ratio for tertiles 2 and 3 versus tertile 1=1.92, 95% confidence interval=1.19-3.09, P<0.01). After additional adjustments in the model, adding established cardiovascular risk factors, confounders of mineral metabolism (calcium, phosphate, parathyroid hormone, and 25 (OH)-vitamin D), and indices of subclinical pathology (flow-mediated vasodilation, endothelial-dependent and -independent vasodilation, arterial stiffness, and atherosclerosis and left ventricular mass) attenuated this relationship, but it remained significant (odds ratio for tertiles 2 and 3 versus tertile 1=1.69, 95% confidence interval=1.01-2.82, P<0.05). Conclusions Fibroblast growth factor-23 is an independent predictor of cardiovascular events in the community, even after accounting for mineral metabolism abnormalities and subclinical cardiovascular damage. Circulating fibroblast growth factor-23 may reflect novel and important aspects of cardiovascular risk yet to be unraveled.

  • 19.
    Arnlöv, Johan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lind, Lars
    Department of Medical Sciences.
    Andrén, Bertil
    Department of Medical Sciences.
    Riserus, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Berglund, L
    Lithell, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    A Doppler-derived index of combined left ventricular systolic and diastolic function is an independent predictor of cardiovascular mortality in elderly men.2005In: Am Heart J, ISSN 1097-6744, Vol. 149, no 5, p. 902-7Article in journal (Refereed)
  • 20.
    Arnlöv, Johan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Department of Public Health and Caring Sciences.
    Sundström, Johan
    Department of Public Health and Caring Sciences.
    Lind, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Andrén, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Andersson, Maria
    Department of Public Health and Caring Sciences.
    Reneland, Richard
    Department of Public Health and Caring Sciences.
    Berglund, Lars
    Kashuba, Vladimir
    Protopopov, Alexei
    Zabarovsky, Eugene
    Lithell, Hans
    Department of Public Health and Caring Sciences.
    hUNC-93B1, a novel gene mainly expressed in the heart, is related to left ventricular diastolic function, heart failure morbidity and mortality in elderly men.2005In: Eur J Heart Fail, ISSN 1388-9842, Vol. 7, no 6, p. 958-65Article in journal (Refereed)
  • 21. Asayama, Kei
    et al.
    Thijs, Lutgarde
    Li, Yan
    Gu, Yu-Mei
    Hara, Azusa
    Liu, Yan-Ping
    Zhang, Zhenyu
    Wei, Fang-Fei
    Lujambio, Ines
    Mena, Luis J.
    Boggia, Jose
    Hansen, Tine W.
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nomura, Kyoko
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Stolarz-Skrzypek, Katarzyna
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    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, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Luzardo, Leonella
    Kawecka-Jaszcz, Kalina
    Sandoya, Edgardo
    Filipovsky, Jan
    Maestre, Gladys E.
    Wang, Jiguang
    Imai, Yutaka
    Franklin, Stanley S.
    O'Brien, Eoin
    Staessen, Jan A.
    Setting Thresholds to Varying Blood Pressure Monitoring Intervals Differentially Affects Risk Estimates Associated With White-Coat and Masked Hypertension in the Population2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 5, p. 935-942Article in journal (Refereed)
    Abstract [en]

    Outcome-driven recommendations about time intervals during which ambulatory blood pressure should be measured to diagnose white-coat or masked hypertension are lacking. We cross-classified 8237 untreated participants (mean age, 50.7 years; 48.4% women) enrolled in 12 population studies, using >= 140/>= 90, >= 130/>= 80, >= 135/>= 85, and >= 120/>= 70 mm Hg as hypertension thresholds for conventional, 24-hour, daytime, and nighttime blood pressure. White-coat hypertension was hypertension on conventional measurement with ambulatory normotension, the opposite condition being masked hypertension. Intervals used for classification of participants were daytime, nighttime, and 24 hours, first considered separately, and next combined as 24 hours plus daytime or plus nighttime, or plus both. Depending on time intervals chosen, white-coat and masked hypertension frequencies ranged from 6.3% to 12.5% and from 9.7% to 19.6%, respectively. During 91 046 person-years, 729 participants experienced a cardiovascular event. In multivariable analyses with normotension during all intervals of the day as reference, hazard ratios associated with white-coat hypertension progressively weakened considering daytime only (1.38; P=0.033), nighttime only (1.43; P=0.0074), 24 hours only (1.21; P=0.20), 24 hours plus daytime (1.24; P=0.18), 24 hours plus nighttime (1.15; P=0.39), and 24 hours plus daytime and nighttime (1.16; P=0.41). The hazard ratios comparing masked hypertension with normotension were all significant (P<0.0001), ranging from 1.76 to 2.03. In conclusion, identification of truly low-risk white-coat hypertension requires setting thresholds simultaneously to 24 hours, daytime, and nighttime blood pressure. Although any time interval suffices to diagnose masked hypertension, as proposed in current guidelines, full 24-hour recordings remain standard in clinical practice.

  • 22.
    Ax, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lampa, Erik
    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.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Circulating levels of environmental contaminants are associated with dietary patterns in older adults2015In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 75, p. 93-102Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Food intake contributes substantially to our exposure to environmental contaminants. Still, little is known about our dietary habits' contribution to exposure variability.

    OBJECTIVE: The aim of this study was to assess circulating levels of environmental contaminants in relation to predefined dietary patterns in an elderly Swedish population.

    METHODS: Dietary data and serum concentrations of environmental contaminants were obtained from 844 70-year-old Swedish subjects (50% women) in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Dietary data from 7-day food records was used to assess adherence to a Mediterranean-like diet, a low carbohydrate-high protein diet and the WHO dietary recommendations. Circulating levels of 6 polychlorinated biphenyl markers, 3 organochlorine pesticides, 1 dioxin and 1 polybrominated diphenyl ether, the metals cadmium, lead, mercury and aluminum and serum levels of bisphenol A and 4 phthalate metabolites were investigated in relation to dietary patterns in multivariate linear regression models.

    RESULTS: A Mediterranean-like diet was positively associated with levels of several polychlorinated biphenyls (118, 126, 153, and 209), trans-nonachlor and mercury. A low carbohydrate-high protein diet was positively associated with polychlorinated biphenyls 118 and 153, trans-nonachlor, hexachlorobenzene and p, p'-dichlorodiphenyldichloroethylene, mercury and lead. The WHO recommended diet was negatively related to levels of dioxin and lead, and borderline positively to polychlorinated biphenyl 118 and trans-nonachlor.

    CONCLUSION: Dietary patterns were associated in diverse manners with circulating levels of environmental contaminants in this elderly Swedish population. Following the WHO dietary recommendations seems to be associated with a lower burden of environmental contaminants.

  • 23.
    Barbu, Andreea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The role of complement factor C3 in lipid metabolism2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 101-107Article, review/survey (Refereed)
    Abstract [en]

    Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.

  • 24.
    Beijer, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    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.
    Nilsson, Peter M.
    SUS Malmo, Dept Clin Sci, Malmo, Sweden..
    Elmstahl, Solve
    Lund Univ, Div Geriatr Med, Dept Hlth Sci, Malmo Univ Hosp, Malmo, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lind, Lars
    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.
    Interaction between physical activity and television time on blood pressure level: cross-sectional data from 45000 individuals2018In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 36, no 5, p. 1041-1050Article in journal (Refereed)
    Abstract [en]

    Objectives:The aim was to investigate if there is an interaction between sitting time and leisure time physical activity on blood pressure and if there are age differences and sex differences in this respect.

    Methods:Linear regression analysis on cross-sectional data was performed in more than 45000 men and women from two Swedish cohort studies, EpiHealth (45-75 years) and LifeGene (18-45 years). Self-reported leisure time physical activity was given in five levels from low (level 1) to vigorous physical activity (level 5) and television time was used as a proxy measure of sitting time.

    Results:High physical activity was associated with lower DBP (P=0.001), but not SBP. Active middle-aged men had lower DBP (-1.1mmHg; 95% CI -1.7 to -0.4) compared with inactive participants. Prolonged television time was associated with higher SBP (P<0.001) and DBP (P=0.011) in both sexes and in most age groups. Watching 3h instead of 1h television per day was associated with higher SBP in middle-aged women (SBP: 1.1mmHg; 95% CI 0.7-1.4) and men (SBP: 1.2mmHg; 95% CI 0.8-1.6). Only in young men, a high physical activity (level 4 instead of level 1) could compensate for a prolonged television time (3h per day) in terms of DBP.

    Conclusion:Prolonged television time was associated with higher SBP and DBP in both sexes and at most ages, whereas an increased physical activity was mainly associated with a lower DBP. Only in young men, a high physical activity could compensate for prolonged television time regarding DBP.

  • 25.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Söderberg, Stefan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    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, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    The fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 11, p. 3955-3959Article in journal (Refereed)
    Abstract [en]

    The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene (FTO) drive the development of obesity in humans are poorly understood. By using C: ross-sectional data from 985 elderly (50% females) who participated at age 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors, circulating levels of ghrelin and leptin were measured after an overnight fast. In addition, subjects were genotyped for FTO rs17817449 (AA, n=345 (35%); AC/CA, n=481 (48.8%); CC, n=159 (16.1%). Linear regression analyses controlling for sex, self-reported physical activity level, fasting plasma glucose, and body mass index were utilized. A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found (P=0.005; relative plasma ghrelin difference between CC and AA carriers = ∼9%). In contrast, serum levels of the satiety enhancing hormone leptin were inversely linked to the number of FTO C risk alleles (P=0.001; relative serum leptin difference between CC and AA carriers = ∼11%). These associations were also found when controlling for waist circumference. The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger promoting hormone ghrelin.

  • 26.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kempton, Matthew J
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Craft, Suzanne
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly2012In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 35, no 3, p. 488-494Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

    RESEARCH DESIGN AND METHODS

    Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume).

    RESULTS

    The HOMA-IR was negatively correlated with verbal fluency performance, brain size (S1), and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses.

    CONCLUSIONS

    These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.

  • 27.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Burgos, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Le Grevès, Madeleine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Association between physical activity and brain health in older adults2013In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 34, no 1, p. 83-90Article in journal (Refereed)
    Abstract [en]

    In the present cross-sectional study, we examined physical activity (PA) and its possible association with cognitive skills and brain structure in 331 cognitively healthy elderly. Based on the number of self-reported light and hard activities for at least 30 minutes per week, participants were assigned to 4 groups representing different levels of PA. The cognitive skills were assessed by the Mini Mental State Examination score, a verbal fluency task, and the Trail-making test as a measure of visuospatial orientation ability. Participants also underwent a magnetic resonance imaging of the brain. Multiple regression analysis revealed that greater PA was associated with a shorter time to complete the Trail-making test, and higher levels of verbal fluency. Further, the level of self-reported PA was positively correlated with brain volume, white matter, as well as a parietal lobe gray matter volume, situated bilaterally at the precuneus. These present cross-sectional results indicate that PA is a lifestyle factor that is linked to brain structure and function in late life.

  • 28.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hogenkamp, Pleunie S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Giedratis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Self-reported sleep disturbance is associated with Alzheimer's disease risk in men2015In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 9, p. 1090-1097Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the association between self-reported sleep disturbances and dementia risk.

    METHODS: Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years.

    RESULTS: Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels.

    CONCLUSION: Improving sleep quality may help reduce the neurodegenerative risk in older men.

  • 29. Bergström, G
    et al.
    Berglund, G
    Blomberg, A
    Brandberg, J
    Engström, G
    Engvall, J
    Eriksson, M
    de Faire, U
    Flinck, A
    Hansson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hedblad, B
    Hjelmgren, O
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jernberg, T
    Johnsson, Å
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Löfdahl, C-G
    Melander, O
    Östgren, C J
    Persson, A
    Persson, M
    Sandström, A
    Schmidt, C
    Söderberg, S
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Toren, K
    Waldenström, A
    Wedel, H
    Vikgren, J
    Fagerberg, B
    Rosengren, A
    The Swedish CArdioPulmonary BioImage Study: objectives and design2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 6, p. 645-659Article in journal (Refereed)
    Abstract [en]

    Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

  • 30. Berndt, Sonja I.
    et al.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maegi, Reedik
    Ganna, Andrea
    Wheeler, Eleanor
    Feitosa, Mary F.
    Justice, Anne E.
    Monda, Keri L.
    Croteau-Chonka, Damien C.
    Day, Felix R.
    Esko, Tonu
    Fall, Tove
    Ferreira, Teresa
    Gentilini, Davide
    Jackson, Anne U.
    Luan, Jian'an
    Randall, Joshua C.
    Vedantam, Sailaja
    Willer, Cristen J.
    Winkler, Thomas W.
    Wood, Andrew R.
    Workalemahu, Tsegaselassie
    Hu, Yi-Juan
    Lee, Sang Hong
    Liang, Liming
    Lin, Dan-Yu
    Min, Josine L.
    Neale, Benjamin M.
    Thorleifsson, Gudmar
    Yang, Jian
    Albrecht, Eva
    Amin, Najaf
    Bragg-Gresham, Jennifer L.
    Cadby, Gemma
    den Heijer, Martin
    Eklund, Niina
    Fischer, Krista
    Goel, Anuj
    Hottenga, Jouke-Jan
    Huffman, Jennifer E.
    Jarick, Ivonne
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johnson, Toby
    Kanoni, Stavroula
    Kleber, Marcus E.
    Koenig, Inke R.
    Kristiansson, Kati
    Kutalik, Zoltn
    Lamina, Claudia
    Lecoeur, Cecile
    Li, Guo
    Mangino, Massimo
    McArdle, Wendy L.
    Medina-Gomez, Carolina
    Mueller-Nurasyid, Martina
    Ngwa, Julius S.
    Nolte, Ilja M.
    Paternoster, Lavinia
    Pechlivanis, Sonali
    Perola, Markus
    Peters, Marjolein J.
    Preuss, Michael
    Rose, Lynda M.
    Shi, Jianxin
    Shungin, Dmitry
    Smith, Albert Vernon
    Strawbridge, Rona J.
    Surakka, Ida
    Teumer, Alexander
    Trip, Mieke D.
    Tyrer, Jonathan
    Van Vliet-Ostaptchouk, Jana V.
    Vandenput, Liesbeth
    Waite, Lindsay L.
    Zhao, Jing Hua
    Absher, Devin
    Asselbergs, Folkert W.
    Atalay, Mustafa
    Attwood, Antony P.
    Balmforth, Anthony J.
    Basart, Hanneke
    Beilby, John
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Bruinenberg, Marcel
    Campbell, Harry
    Chasman, Daniel I.
    Chines, Peter S.
    Collins, Francis S.
    Connell, John M.
    Cookson, William O.
    de Faire, Ulf
    de Vegt, Femmie
    Dei, Mariano
    Dimitriou, Maria
    Edkins, Sarah
    Estrada, Karol
    Evans, David M.
    Farrall, Martin
    Ferrario, Marco M.
    Ferrieres, Jean
    Franke, Lude
    Frau, Francesca
    Gejman, Pablo V.
    Grallert, Harald
    Groenberg, Henrik
    Gudnason, Vilmundur
    Hall, Alistair S.
    Hall, Per
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Heard-Costa, Nancy L.
    Heath, Andrew C.
    Hebebrand, Johannes
    Homuth, Georg
    Hu, Frank B.
    Hunt, Sarah E.
    Hyppoenen, Elina
    Iribarren, Carlos
    Jacobs, Kevin B.
    Jansson, John-Olov
    Jula, Antti
    Kahonen, Mika
    Kathiresan, Sekar
    Kee, Frank
    Khaw, Kay-Tee
    Kivimaki, Mika
    Koenig, Wolfgang
    Kraja, Aldi T.
    Kumari, Meena
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laitinen, Jaana H.
    Lakka, Timo A.
    Langenberg, Claudia
    Launer, Lenore J.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindstrom, Jaana
    Liu, Jianjun
    Liuzzi, Antonio
    Lokki, Marja-Liisa
    Lorentzon, Mattias
    Madden, Pamela A.
    Magnusson, Patrik K.
    Manunta, Paolo
    Marek, Diana
    Maerz, Winfried
    Leach, Irene Mateo
    McKnight, Barbara
    Medland, Sarah E.
    Mihailov, Evelin
    Milani, Lili
    Montgomery, Grant W.
    Mooser, Vincent
    Muehleisen, Thomas W.
    Munroe, Patricia B.
    Musk, Arthur W.
    Narisu, Narisu
    Navis, Gerjan
    Nicholson, George
    Nohr, Ellen A.
    Ong, Ken K.
    Oostra, Ben A.
    Palmer, Colin N. A.
    Palotie, Aarno
    Peden, John F.
    Pedersen, Nancy
    Peters, Annette
    Polasek, Ozren
    Pouta, Anneli
    Pramstaller, Peter P.
    Prokopenko, Inga
    Puetter, Carolin
    Radhakrishnan, Aparna
    Raitakari, Olli
    Rendon, Augusto
    Rivadeneira, Fernando
    Rudan, Igor
    Saaristo, Timo E.
    Sambrook, Jennifer G.
    Sanders, Alan R.
    Sanna, Serena
    Saramies, Jouko
    Schipf, Sabine
    Schreiber, Stefan
    Schunkert, Heribert
    Shin, So-Youn
    Signorini, Stefano
    Sinisalo, Juha
    Skrobek, Boris
    Soranzo, Nicole
    Stancakova, Alena
    Stark, Klaus
    Stephens, Jonathan C.
    Stirrups, Kathleen
    Stolk, Ronald P.
    Stumvoll, Michael
    Swift, Amy J.
    Theodoraki, Eirini V.
    Thorand, Barbara
    Tregouet, David-Alexandre
    Tremoli, Elena
    Van der Klauw, Melanie M.
    van Meurs, Joyce B. J.
    Vermeulen, Sita H.
    Viikari, Jorma
    Virtamo, Jarmo
    Vitart, Veronique
    Waeber, Gerard
    Wang, Zhaoming
    Widen, Elisabeth
    Wild, Sarah H.
    Willemsen, Gonneke
    Winkelmann, Bernhard R.
    Witteman, Jacqueline C. M.
    Wolffenbuttel, Bruce H. R.
    Wong, Andrew
    Wright, Alan F.
    Zillikens, M. Carola
    Amouyel, Philippe
    Boehm, Bernhard O.
    Boerwinkle, Eric
    Boomsma, Dorret I.
    Caulfield, Mark J.
    Chanock, Stephen J.
    Cupples, L. Adrienne
    Cusi, Daniele
    Dedoussis, George V.
    Erdmann, Jeanette
    Eriksson, Johan G.
    Franks, Paul W.
    Froguel, Philippe
    Gieger, Christian
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hamsten, Anders
    Harris, Tamara B.
    Hengstenberg, Christian
    Hicks, Andrew A.
    Hingorani, Aroon
    Hinney, Anke
    Hofman, Albert
    Hovingh, Kees G.
    Hveem, Kristian
    Illig, Thomas
    Jarvelin, Marjo-Riitta
    Joeckel, Karl-Heinz
    Keinanen-Kiukaanniemi, Sirkka M.
    Kiemeney, Lambertus A.
    Kuh, Diana
    Laakso, Markku
    Lehtimaki, Terho
    Levinson, Douglas F.
    Martin, Nicholas G.
    Metspalu, Andres
    Morris, Andrew D.
    Nieminen, Markku S.
    Njolstad, Inger
    Ohlsson, Claes
    Oldehinkel, Albertine J.
    Ouwehand, Willem H.
    Palmer, Lyle J.
    Penninx, Brenda
    Power, Chris
    Province, Michael A.
    Psaty, Bruce M.
    Qi, Lu
    Rauramaa, Rainer
    Ridker, Paul M.
    Ripatti, Samuli
    Salomaa, Veikko
    Samani, Nilesh J.
    Snieder, Harold
    Sorensen, Thorkild I. A.
    Spector, Timothy D.
    Stefansson, Kari
    Tonjes, Anke
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Matti
    van der Harst, Pim
    Vollenweider, Peter
    Wallaschofski, Henri
    Wareham, Nicholas J.
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F.
    Abecasis, Goncalo R.
    Assimes, Themistocles L.
    Barroso, Ines
    Boehnke, Michael
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Frayling, Timothy
    Groop, Leif C.
    Haritunian, Talin
    Heid, Iris M.
    Hunter, David
    Kaplan, Robert C.
    Karpe, Fredrik
    Moffatt, Miriam F.
    Mohlke, Karen L.
    O'Connell, Jeffrey R.
    Pawitan, Yudi
    Schadt, Eric E.
    Schlessinger, David
    Steinthorsdottir, Valgerdur
    Strachan, David P.
    Thorsteinsdottir, Unnur
    van Duijn, Cornelia M.
    Visscher, Peter M.
    Di Blasio, Anna Maria
    Hirschhorn, Joel N.
    Lindgren, Cecilia M.
    Morris, Andrew P.
    Meyre, David
    Scherag, Andr
    McCarthy, Mark I.
    Speliotes, Elizabeth K.
    North, Kari E.
    Loos, Ruth J. F.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 5, p. 501-U69Article in journal (Refereed)
    Abstract [en]

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

  • 31. Berndt, Sonja I.
    et al.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maegi, Reedik
    Ganna, Andrea
    Wheeler, Eleanor
    Feitosa, Mary F.
    Justice, Anne E.
    Monda, Keri L.
    Croteau-Chonka, Damien C.
    Day, Felix R.
    Esko, Tonu
    Fall, Tove
    Ferreira, Teresa
    Gentilini, Davide
    Jackson, Anne U.
    Luan, Jian'an
    Randall, Joshua C.
    Vedantam, Sailaja
    Willer, Cristen J.
    Winkler, Thomas W.
    Wood, Andrew R.
    Workalemahu, Tsegaselassie
    Hu, Yi-Juan
    Lee, Sang Hong
    Liang, Liming
    Lin, Dan-Yu
    Min, Josine L.
    Neale, Benjamin M.
    Thorleifsson, Gudmar
    Yang, Jian
    Albrecht, Eva
    Amin, Najaf
    Bragg-Gresham, Jennifer L.
    Cadby, Gemma
    den Heijer, Martin
    Eklund, Niina
    Fischer, Krista
    Goel, Anuj
    Hottenga, Jouke-Jan
    Huffman, Jennifer E.
    Jarick, Ivonne
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johnson, Toby
    Kanoni, Stavroula
    Kleber, Marcus E.
    Koenig, Inke R.
    Kristiansson, Kati
    Kutalik, Zoltn
    Lamina, Claudia
    Lecoeur, Cecile
    Li, Guo
    Mangino, Massimo
    McArdle, Wendy L.
    Medina-Gomez, Carolina
    Mueller-Nurasyid, Martina
    Ngwa, Julius S.
    Nolte, Ilja M.
    Paternoster, Lavinia
    Pechlivanis, Sonali
    Perola, Markus
    Peters, Marjolein J.
    Preuss, Michael
    Rose, Lynda M.
    Shi, Jianxin
    Shungin, Dmitry
    Smith, Albert Vernon
    Strawbridge, Rona J.
    Surakka, Ida
    Teumer, Alexander
    Trip, Mieke D.
    Tyrer, Jonathan
    Van Vliet-Ostaptchouk, Jana V.
    Vandenput, Liesbeth
    Waite, Lindsay L.
    Zhao, Jing Hua
    Absher, Devin
    Asselbergs, Folkert W.
    Atalay, Mustafa
    Attwood, Antony P.
    Balmforth, Anthony J.
    Basart, Hanneke
    Beilby, John
    Bonnycastle, Lori L.
    Brambilla, Paolo
    Bruinenberg, Marcel
    Campbell, Harry
    Chasman, Daniel I.
    Chines, Peter S.
    Collins, Francis S.
    Connell, John M.
    Cookson, William O.
    de Faire, Ulf
    de Vegt, Femmie
    Dei, Mariano
    Dimitriou, Maria
    Edkins, Sarah
    Estrada, Karol
    Evans, David M.
    Farrall, Martin
    Ferrario, Marco M.
    Ferrieres, Jean
    Franke, Lude
    Frau, Francesca
    Gejman, Pablo V.
    Grallert, Harald
    Groenberg, Henrik
    Gudnason, Vilmundur
    Hall, Alistair S.
    Hall, Per
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Heard-Costa, Nancy L.
    Heath, Andrew C.
    Hebebrand, Johannes
    Homuth, Georg
    Hu, Frank B.
    Hunt, Sarah E.
    Hyppoenen, Elina
    Iribarren, Carlos
    Jacobs, Kevin B.
    Jansson, John-Olov
    Jula, Antti
    Kahonen, Mika
    Kathiresan, Sekar
    Kee, Frank
    Khaw, Kay-Tee
    Kivimaki, Mika
    Koenig, Wolfgang
    Kraja, Aldi T.
    Kumari, Meena
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Laitinen, Jaana H.
    Lakka, Timo A.
    Langenberg, Claudia
    Launer, Lenore J.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindstrom, Jaana
    Liu, Jianjun
    Liuzzi, Antonio
    Lokki, Marja-Liisa
    Lorentzon, Mattias
    Madden, Pamela A.
    Magnusson, Patrik K.
    Manunta, Paolo
    Marek, Diana
    Maerz, Winfried
    Leach, Irene Mateo
    McKnight, Barbara
    Medland, Sarah E.
    Mihailov, Evelin
    Milani, Lili
    Montgomery, Grant W.
    Mooser, Vincent
    Muehleisen, Thomas W.
    Munroe, Patricia B.
    Musk, Arthur W.
    Narisu, Narisu
    Navis, Gerjan
    Nicholson, George
    Nohr, Ellen A.
    Ong, Ken K.
    Oostra, Ben A.
    Palmer, Colin N. A.
    Palotie, Aarno
    Peden, John F.
    Pedersen, Nancy
    Peters, Annette
    Polasek, Ozren
    Pouta, Anneli
    Pramstaller, Peter P.
    Prokopenko, Inga
    Puetter, Carolin
    Radhakrishnan, Aparna
    Raitakari, Olli
    Rendon, Augusto
    Rivadeneira, Fernando
    Rudan, Igor
    Saaristo, Timo E.
    Sambrook, Jennifer G.
    Sanders, Alan R.
    Sanna, Serena
    Saramies, Jouko
    Schipf, Sabine
    Schreiber, Stefan
    Schunkert, Heribert
    Shin, So-Youn
    Signorini, Stefano
    Sinisalo, Juha
    Skrobek, Boris
    Soranzo, Nicole
    Stancakova, Alena
    Stark, Klaus
    Stephens, Jonathan C.
    Stirrups, Kathleen
    Stolk, Ronald P.
    Stumvoll, Michael
    Swift, Amy J.
    Theodoraki, Eirini V.
    Thorand, Barbara
    Tregouet, David-Alexandre
    Tremoli, Elena
    Van der Klauw, Melanie M.
    van Meurs, Joyce B. J.
    Vermeulen, Sita H.
    Viikari, Jorma
    Virtamo, Jarmo
    Vitart, Veronique
    Waeber, Gerard
    Wang, Zhaoming
    Widen, Elisabeth
    Wild, Sarah H.
    Willemsen, Gonneke
    Winkelmann, Bernhard R.
    Witteman, Jacqueline C. M.
    Wolffenbuttel, Bruce H. R.
    Wong, Andrew
    Wright, Alan F.
    Zillikens, M. Carola
    Amouyel, Philippe
    Boehm, Bernhard O.
    Boerwinkle, Eric
    Boomsma, Dorret I.
    Caulfield, Mark J.
    Chanock, Stephen J.
    Cupples, L. Adrienne
    Cusi, Daniele
    Dedoussis, George V.
    Erdmann, Jeanette
    Eriksson, Johan G.
    Franks, Paul W.
    Froguel, Philippe
    Gieger, Christian
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hamsten, Anders
    Harris, Tamara B.
    Hengstenberg, Christian
    Hicks, Andrew A.
    Hingorani, Aroon
    Hinney, Anke
    Hofman, Albert
    Hovingh, Kees G.
    Hveem, Kristian
    Illig, Thomas
    Jarvelin, Marjo-Riitta
    Joeckel, Karl-Heinz
    Keinanen-Kiukaanniemi, Sirkka M.
    Kiemeney, Lambertus A.
    Kuh, Diana
    Laakso, Markku
    Lehtimaki, Terho
    Levinson, Douglas F.
    Martin, Nicholas G.
    Metspalu, Andres
    Morris, Andrew D.
    Nieminen, Markku S.
    Njolstad, Inger
    Ohlsson, Claes
    Oldehinkel, Albertine J.
    Ouwehand, Willem H.
    Palmer, Lyle J.
    Penninx, Brenda
    Power, Chris
    Province, Michael A.
    Psaty, Bruce M.
    Qi, Lu
    Rauramaa, Rainer
    Ridker, Paul M.
    Ripatti, Samuli
    Salomaa, Veikko
    Samani, Nilesh J.
    Snieder, Harold
    Sorensen, Thorkild I. A.
    Spector, Timothy D.
    Stefansson, Kari
    Tonjes, Anke
    Tuomilehto, Jaakko
    Uitterlinden, Andre G.
    Uusitupa, Matti
    van der Harst, Pim
    Vollenweider, Peter
    Wallaschofski, Henri
    Wareham, Nicholas J.
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F.
    Abecasis, Goncalo R.
    Assimes, Themistocles L.
    Barroso, Ines
    Boehnke, Michael
    Borecki, Ingrid B.
    Deloukas, Panos
    Fox, Caroline S.
    Frayling, Timothy
    Groop, Leif C.
    Haritunian, Talin
    Heid, Iris M.
    Hunter, David
    Kaplan, Robert C.
    Karpe, Fredrik
    Moffatt, Miriam F.
    Mohlke, Karen L.
    O'Connell, Jeffrey R.
    Pawitan, Yudi
    Schadt, Eric E.
    Schlessinger, David
    Steinthorsdottir, Valgerdur
    Strachan, David P.
    Thorsteinsdottir, Unnur
    van Duijn, Cornelia M.
    Visscher, Peter M.
    Di Blasio, Anna Maria
    Hirschhorn, Joel N.
    Lindgren, Cecilia M.
    Morris, Andrew P.
    Meyre, David
    Scherag, Andr
    McCarthy, Mark I.
    Speliotes, Elizabeth K.
    North, Kari E.
    Loos, Ruth J. F.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 5, p. 501-U69Article in journal (Refereed)
    Abstract [en]

    Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

  • 32.
    Björklund, Kristina
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lind, Lars
    Department of Medical Sciences.
    Andren, Bertil
    Department of Medical Sciences.
    Lithell, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Public Health and Caring Sciences.
    The majority of nondipping men do not have increased cardiovascular risk: a population-based study.2002In: J Hypertens, ISSN 0263-6352, Vol. 20, no 8, p. 1501-6Article in journal (Refereed)
  • 33.
    Björklund, Kristina
    et al.
    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.
    Vessby, Bengt
    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.
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Different metabolic predictors of white-coat and sustained hypertension over a 20-year follow-up period: a population-based study of elderly men2002In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 106, no 1, p. 63-68Article in journal (Refereed)
    Abstract [en]

    Background The clinical significance of white-coat hypertension is still unclear. Moreover, no study has examined metabolic predictors of white-coat versus sustained hypertension.

    Methods and Results We investigated men (n=602) in a longitudinal population-based cohort who at age 70 years were identified as normotensive, white-coat hypertensive (office blood pressure [BP] ≥140/90 and daytime ambulatory BP <135/85 mm Hg), and sustained hypertensive (office BP ≥140/90 and daytime ambulatory BP ≥135/85 mm Hg). At baseline, when the subjects were aged 50 years, blood glucose, insulin, lipids, and fatty acid composition of the serum cholesterol esters were analyzed. The investigations at age 70 years included determination of insulin sensitivity and target organ damage. At age 50 years, individuals who 20 years later were identified as white-coat hypertensive or sustained hypertensive showed significantly elevated BP, heart rate, and impaired glucose tolerance compared with normotensive subjects but white coat hypertensive subjects were leaner and had a more favorable serum cholesterol ester fatty acid profile than did sustained hypertensive subjects. At age 70 years, both white-coat and sustained hypertensive subjects showed an impaired insulin sensitivity, elevated blood glucose, and increased serum insulin and heart rate compared with normotensive subjects, but left ventricular mass and urinary albumin excretion were increased only in sustained hypertensive subjects.

    Conclusions These findings indicate that although metabolic abnormalities and elevated heart rate were consistent over time in both hypertensive groups, a lower body mass index and more favorable dietary fat composition predicted the development of white-coat as opposed to sustained hypertension over 20 years.

  • 34.
    Björklund, Kristina
    et al.
    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.
    Zethelius, Björn
    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.
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men2003In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 107, no 9, p. 1297-302Article in journal (Refereed)
    Abstract [en]

    Background— Little is known about isolated ambulatory hypertension, a state with elevated ambulatory but normal office blood pressure (BP). This study aimed to investigate the prognostic significance of isolated ambulatory hypertension for cardiovascular morbidity in a population of elderly men.

    Methods and Results— At baseline, 24-hour ambulatory BP and metabolic and cardiac risk profiles were evaluated in 578 untreated 70-year-old men, participants of a population-based cohort. Subjects with isolated ambulatory hypertension (office BP <140/90 and daytime BP ≥135/85) and sustained hypertension (office BP ≥140/90 and daytime BP ≥135/85) had increased plasma glucose, body mass index, and echocardiographically determined left ventricular relative wall thickness compared with normotensive subjects (office BP <140/90 and daytime BP <135/85). Seventy-two cardiovascular morbid events (2.37 per 100 person-years at risk) occurred over 8.4 years of follow-up. The prognostic value of isolated ambulatory and sustained hypertension was assessed with Cox proportional hazard regression. Multivariate models adjusting for serum cholesterol, smoking, and diabetes demonstrated that both isolated ambulatory hypertension (hazard ratio [HR], 2.77; 95% CI, 1.15 to 6.68) and sustained hypertension (HR, 2.94; 95% CI, 1.49 to 5.82) were independent predictors of cardiovascular morbidity. In a multivariate model with continuous BP variables, ambulatory daytime systolic BP (HR for 1 SD increase, 1.47; 95% CI, 1.09 to 1.97) was associated with an adverse outcome independently of office systolic BP.

    Conclusions— In the present study, isolated ambulatory hypertension as well as sustained hypertension predicted cardiovascular morbidity. The findings suggest that 24-hour ambulatory BP monitoring may disclose important prognostic information also in subjects characterized as normotensive according to office BP.

  • 35. Björklund, Kristina
    et al.
    Lind, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Zethelius, Björn
    Berglund, Lars
    Lithell, Hans
    Prognostic significance of 24-h ambulatory blood pressure characteristics for cardiovascular morbidity in a population of elderly men.2004In: J Hypertens, ISSN 0263-6352, Vol. 22, no 9, p. 1691-7Article in journal (Refereed)
  • 36. Boggia, Jose
    et al.
    Thijs, Lutgarde
    Li, Yan
    Hansen, Tine W.
    Kikuya, Masahiro
    Bjorklund-Bodegard, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schwedt, Emma
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Risk Stratification by 24-Hour Ambulatory Blood Pressure and Estimated Glomerular Filtration Rate in 5322 Subjects From 11 Populations2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 61, no 1, p. 18-+Article in journal (Refereed)
    Abstract [en]

    No previous study addressed whether in the general population estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration formula]) adds to the prediction of cardiovascular outcome over and beyond ambulatory blood pressure. We recorded health outcomes in 5322 subjects (median age, 51.8 years; 43.1% women) randomly recruited from 11 populations, who had baseline measurements of 24-hour ambulatory blood pressure (ABP(24)) and eGFR. We computed hazard ratios using multivariable-adjusted Cox regression. Median follow-up was 9.3 years. In fully adjusted models, which included both ABP(24) and eGFR, ABP(24) predicted (P <= 0.008) both total (513 deaths) and cardiovascular (206) mortality; eGFR only predicted cardiovascular mortality (P=0.012). Furthermore, ABP(24) predicted (P <= 0.0056) fatal combined with nonfatal events as a result of all cardiovascular causes (555 events), cardiac disease (335 events), or stroke (218 events), whereas eGFR only predicted the composite cardiovascular end point and stroke (P <= 0.035). The interaction terms between ABP(24) and eGFR were all nonsignificant (P >= 0.082). For cardiovascular mortality, the composite cardiovascular end point, and stroke, ABP(24) added 0.35%, 1.17%, and 1.00% to the risk already explained by cohort, sex, age, body mass index, smoking and drinking, previous cardiovascular disease, diabetes mellitus, and antihypertensive drug treatment. Adding eGFR explained an additional 0.13%, 0.09%, and 0.14%, respectively. Sensitivity analyses stratified for ethnicity, sex, and the presence of hypertension or chronic kidney disease (eGFR <60mL/min per 1.73 m(2)) were confirmatory. In conclusion, in the general population, eGFR predicts fewer end points than ABP(24). Relative to ABP(24), eGFR is as an additive, not a multiplicative, risk factor and refines risk stratification 2-to14-fold less.

  • 37. Bolton, Jennifer L.
    et al.
    Hayward, Caroline
    Direk, Nese
    Lewis, John G.
    Hammond, Geoffrey L.
    Hill, Lesley A.
    Anderson, Anna
    Huffman, Jennifer
    Wilson, James F.
    Campbell, Harry
    Rudan, Igor
    Wright, Alan
    Hastie, Nicholas
    Wild, Sarah H.
    Velders, Fleur P.
    Hofman, Albert
    Uitterlinden, Andre G.
    Lahti, Jari
    Raikkonen, Katri
    Kajantie, Eero
    Widen, Elisabeth
    Palotie, Aarno
    Eriksson, Johan G.
    Kaakinen, Marika
    Jarvelin, Marjo-Riitta
    Timpson, Nicholas J.
    Smith, George Davey
    Ring, Susan M.
    Evans, David M.
    St Pourcain, Beate
    Tanaka, Toshiko
    Milaneschi, Yuri
    Bandinelli, Stefania
    Ferrucci, Luigi
    van der Harst, Pim
    Rosmalen, Judith G. M.
    Bakker, Stephen J. L.
    Verweij, Niek
    Dullaart, Robin P. F.
    Mahajan, Anubha
    Lindgren, Cecilia M.
    Morris, Andrew
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Anderson, Laura N.
    Pennell, Craig E.
    Lye, Stephen J.
    Matthews, Stephen G.
    Eriksson, Joel
    Mellstrom, Dan
    Ohlsson, Claes
    Price, Jackie F.
    Strachan, Mark W. J.
    Reynolds, Rebecca M.
    Tiemeier, Henning
    Walker, Brian R.
    Genome Wide Association Identifies Common Variants at the SERPINA6/SERPINA1 Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin2014In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 7Article in journal (Refereed)
    Abstract [en]

    Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding alpha 1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.

  • 38. Brguljan-Hitij, Jana
    et al.
    Thijs, Lutgarde
    Li, Yan
    Hansen, Tine W.
    Boggia, Jose
    Liu, Yan-Ping
    Asayama, Kei
    Wei, Fang-Fei
    Bjorklund-Bodegard, Kristina
    Gu, Yu-Mei
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Wang, Jiguang
    O'Brien, Eoin
    Staessen, Jan A.
    Risk Stratification by Ambulatory Blood Pressure Monitoring Across JNC Classes of Conventional Blood Pressure2014In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, no 7, p. 956-965Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Guidelines propose classification of conventional blood pressure (CBP) into normotension (<120/<80 mm Hg), prehypertension (120-139/80-89 mm Hg), and hypertension (>140/>90 mm Hg). METHODS To assess the potential differential contribution of ambulatory blood pressure (ABP) in predicting risk across CBP strata, we analyzed outcomes in 7,826 untreated people recruited from 11 populations. RESULTS During an 11.3-year period, 809 participants died (276 cardiovascular deaths) and 639, 383, and 225 experienced a cardiovascular, cardiac, or cerebrovascular event. Compared with normotension (n = 2,639), prehypertension (n = 3,076) carried higher risk (P <= 0.015) of cardiovascular (+ 41%) and cerebrovascular (+ 92%) endpoints; compared with hypertension (n = 2,111) prehypertension entailed lower risk (P <= 0.005) of total mortality (-14%) and cardiovascular mortality (-29%) and of cardiovascular (-34%), cardiac (-33%), or cerebrovascular (-47%) events. Multivariable-adjusted hazard ratios (HRs) for stroke associated with 24-hour and daytime diastolic ABP (+ 5 mm Hg) were higher (P <= 0.045) in normotension than in prehypertension and hypertension (1.98 vs. 1.19 vs. 1.28 and 1.73 vs. 1.09 vs. 1.24, respectively) with similar trends (0.03 <= P <= 0.11) for systolic ABP (+10 mm Hg). However, HRs for fatal endpoints and cardiac events associated with ABP did not differ significantly (P >= 0.13) across CBP categories. Of normotensive and prehypertensive participants, 7.5% and 29.3% had masked hypertension (daytime ABP >= 135/>= 85 mm Hg). Compared with true normotension (P <= 0.01), HRs for stroke were 3.02 in normotension and 2.97 in prehypertension associated with masked hypertension with no difference between the latter two conditions (P = 0.93). CONCLUSION ABP refines risk stratification in normotension and prehypertension mainly by enabling the diagnosis of masked hypertension.

  • 39.
    Brittebo, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Helén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Monica
    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.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Bioactivation and effects of environmental pollutants in human and rodent blood vessel endothelial cells2012In: Organohalogen compound database (http://www.dioxin20xx.org/ohc_database_search.htm), 2012Conference paper (Refereed)
    Abstract [en]

    Introduction

    Recent epidemiological studies reveal associations between exposure to environmental pollutants and cardiovascular disorders in humans. Elevated serum concentrations of polychlorinated biphenyls (PCBs) have for instance been associated with cardiovascular risk factors such as hypertension (1-3). Exposure to the carbonate plastic monomer bisphenol A (BPA) has been associated with an increased incidence of cardiovascular disease and atherogenic changes in the vascular wall (4-6). The contention that the human cardiovascular system is a sensitive target for toxic chemicals gain support from our earlier and recent experimental studies in rodents, birds and fish, as well as in cultured human primary endothelial cells. It is also compatible with earlier observations that certain polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens that may also contribute to atherosclerosis in mice and birds (7,8).

    In this presentation we will briefly discuss effects of Ah receptor (AhR) agonists (e.g. the coplanar PCB126 or BNF, ß-naphthoflavone) on the expression of cytochrome P450 (CYP)1 enzymes in various endothelia in rodents in vivo or ex vivo, as well as in cultured human umbilical vein endothelial cells (HUVEC). The CYP1-dependent bioactivation and irreversible binding of prototype polyaromatic hydrocarbons (PAH) and heterocyclic amines such as benzo(a)pyrene (BaP), 7,12-dimethyl- benz(a)anthracene (DMBA) and 3-amino-1,4-dimethyl-5H-pyrido- [4,3-b]indole (Trp-P1) in these endothelia will be reviewed. We will also report how PCB126 affects vasoactive factors in HUVEC, and how these effects are modulated by physiological 17ß-oestradiol concentrations. Some effects of PCB126, 1-nitropyrene (1-NP) and bisphenol A (BPA) on biomarkers for endothelial dysfunction, cell stress and DNA damage in HUVEC will finally be presented.

    Material and methods

    Human umbilical vein endothelial cells (HUVEC) were purchased from Science Cell Research laboratories, Carlsbad, CA. C57Bl mice and Wistar or Sprague Dawley rats were purchased from various suppliers. All animal experiments were approved by the Local Ethical Committee for Research on Animals in Uppsala and the studies followed the guidelines laid down by the Swedish and European Union legislation on animal experimentation. Rodents, tissue-slices and cultured cells were treated with model chemicals as previously described. Tape section and light microscopy autoradiographic imaging using 3H-labelled BaP, DMBA and Trp-P-1 and immunohistochemistry was performed as previously described (9-19). Precision-cut tissue slices for in vitro autoradiography were prepared as described in (14) and the slices were incubated with various 3H-labelled chemicals. HUVEC were exposed to various compounds and the detection of biomarkers of endothelial dysfunction, DNA damage were performed as described (20-22). Finally, female Fischer rats were exposed to BPA (0.025, 0.25 and 2.5 mg/l) and fructose (50 g/l) in the drinking water from 5 to 15 weeks of age to mimic human exposure (unpublished data).

    Results and discussion

    Co-localization of CYP1A1 expression and BaP, DMBA and Trp-P-1 adduct formation in endothelial linings As demonstrated by immunohistochemistry, a high CYP1A immunoreactivity occurred in capillaries of the heart, skeletal muscle, uterus and in blood-brain interfaces such as the leptomeninges and plexus choroideus, whereas no expression was observed for instance in cerebral capillary endothelial cells of mice treated with AhR agonists (9-11). No, or very low constitutive immunoreactivities were observed in these endothelia in vehicle-treated animals. No basal or induced CYP1B1 expression was observed in endothelial cells, while a weak CYP1B1 immunostaining was detected in the muscle layer of small arteries. It should be noted that in subcellular preparations of whole organs, e.g. heart and brain, the CYP1A1 in endothelial cells is diluted due to cells that do not express high levels of CYP1A1, for examples myocytes or neurons, in excess. A cell-specific metabolism in endothelial cells may therefore remain undetected due to the presence of metabolically inactive cells. In order to detect minor sites of bioactivation such as endothelial linings we employed light microscopic autoradiographic imaging to examine the bioactivation and subsequent irreversible binding of the radiolabelled prototype toxicants in tissues of animals pretreated with AhR-agonists. As determined by light microscopic autoradiography of AhR-agonist-treated mice exposed to 3H-labelled BaP, DMBA or Trp-P-1 and birds exposed to 3H-Trp-P-1 a significant accumulation of non-extractable radioactivity occurred in endothelial linings (9-18). The bound radioactivity occurred in the nuclei and the perinuclear cytoplasm, suggesting that the autoradiograms depict both DNA- and protein-bound adducts. Since the binding sites of 3H-labelled BaP, DMBA or Trp-P-1 corresponded with the sites of CYP1A1 induction, we concluded that rodents express a constitutively low but highly inducible and functional CYP1A1 in endothelial cells. The binding of reactive metabolites in endothelial cells exceeded the binding in all other cell types in AhR-agonist treated mice and was abolished by pretreatment with the CYP1A1 inhibitor ellipticine, supporting a CYP1A1-catalysed metabolic activation in situ to a reactive species (9, 10,12). These findings imply that there is a preferential CYP1A1-catalysed formation of reactive metabolites from all three carcinogens in endothelial cells expressing high CYP1A1 levels. Interestingly, however, carcinogenesis in endothelial cells is a relative rare finding, suggesting that degenerative lesions and cell death may be more prevalent responses to metabolism-activated carcinogens/mutagens in these cells. Experiments with 3H-DMBA and 3H-Trp-P-1 in HUVEC confirmed that AhR-agonists induced an increased bioactivation, suggesting that also human endothelial cells should be targets for toxicity of reactive intermediates formed from CYP1A1- activated carcinogens/mutagens (17-18). This conclusion is supported by immunohistochemical studies on the heavily vascularized human endometrium demonstrating an expression of CYP1A1 and CYP1B1 protein in and around human endometrial blood vessels, although a large interindividual

    variation was observed (19). None of the endometrial biopsy samples displayed vascular expression of CYP2A6, CYP2B6, CYP2C8/2C9/2C19, CYP2D6, or CYP3A4/5 protein.

    Effects of PCB 126, 1-NP, and BPA on biomarkers of endothelial dysfunction and cell stress in endothelial cells In vitro studies demonstrated that PCB126 increased the levels of vasoconstriction factors and decreased the levels of vasodilating factors in cultured HUVEC in a fashion that is characteristic for endothelial dysfunction related to human hypertension. The study showed that the co-planar PCB126 induced expression of the endothelium-derived vasoconstriction factor COX-2 and stimulated formation of the vasoconstrictor prostaglandin PGF2 via the AhR in HUVEC (20). COX-2 is known to play a role in hypertension by catalysing the formation of vasoconstriction prostaglandins and by stimulating reactive oxygen species (ROS) production. Further studies demonstrated that PCB126 increased the production of the vasoconstriction prostaglandin PGF2 and ROS in HUVEC. The relationship between increased ROS production and human hypertension is well established, ROS promotes vasoconstriction by stimulating the production of vasoconstriction prostaglandins and by reducing bioavailability of the vasorelaxing factor NO. Indeed, exposure to PCB126 slightly reduced the production of NO in HUVEC. Furthermore, the PCB126-induced mRNA expressions of CYP1A1, CYP1B1 and COX-2 in HUVEC were enhanced in the presence of physiological levels of 17- estradiol. This suggests that increased levels of oestrogen stimulate AhR-dependent transcription of genes previously associated with endothelial dysfunction and hypertension.

    In another study we have examined the effects of a nitrated PAH, 1-nitropyrene, that is abundant in diesel exhausts (21). The results revealed that 1-NP induced DNA damage, increased levels of ROS and increased protein expression of the endoplasmic reticulum stress chaperone GRP78 in cultured HUVEC. Induction of CYP1A1 by PCB126 as well as inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction and not by CYP1-dependent bioactivation to reactive intermediates.

    Recent in vitro studies demonstrated that bisphenol A increased the mRNA expression of genes that regulate vasoconstriction and angiogenesis in HUVEC (eNOS, VEGF, VEGFR2, connexin 43 and ACE1) and in human cardiomyocytes (eNOS and ACE1) (22). The results also showed that BPA increased the expression of P-eNOS(ser1177) and the production of NO in HUVEC. NO is the main effector molecule in angiogenesis downstream of VEGF. Based on the findings that BPA increase the expression of proangiogenic factors we investigated whether BPA could stimulate in vitro angiogenesis in HUVEC using the endothelial tube formation assay. The results demonstrated that BPA increased HUVEC tube formation suggesting that BPA can act directly on the endothelium and stimulate angiogenesis. Long-term exposure in rats revealed that environmentally relevant levels of BPA, increased the cardiac mRNA expression of genes that regulate vasoconstriction and angiogenesis. Ten weeks exposure of rats from preadolescence to adulthood to BPA in the drinking water increased the

    expression of eNOS, VEGF, VEGFR2 and ACE1 in the heart. Taken together, the genes that were upregulated in rat cardiac tissues in vivo were also upregulated in human endothelial cells and cardiomyocytes in vitro. The heart is a heavily vascularized tissue that consists mainly of cardiac endothelial cells and cardiomyocytes and although cardiomyocytes dominate the volume of the myocardium the number of endothelial cells exceeds the number of cardiomyocytes by approximately three to one. Thus, the effects of BPA on eNOS VEGF, VEGFR2 and ACE1 mRNA expression in rat cardiac tissues are most likely to be related to an effect of BPA on endothelial cells but may also involve cardiomyocytes.

    We conclude that endothelial cells may be targets for bioactivation and toxicity of environmental pollutants. The immunohistochemical and autoradiographic data demonstrated a differential expression of CYP1 enzymes and metabolic activation of pollutants in various endothelial linings suggesting that some but not all endothelial linings may be targets for xenobiotics metabolised by AhR-regulated enzymes. Studies on the effects of PCB126, 1-nitropyrene and BPA in cultured human primary endothelial cells demonstrated up-regulation of various biomarkers for endothelial dysfunction and cell stress suggesting that the human endothelium may be a sensitive target for these pollutants. The bioactivation and effects of environmental pollutants in endothelial cells should be further studied in order to unravel the role of these chemicals in human cardiovascular disease.

  • 40.
    Brooks, Samantha J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Burgos, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kempton, M J
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    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.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Late-life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study2013In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 37, no 2, p. 230-236Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: 

    Obesity adversely affects frontal lobe brain structure and function. Here we sought to show that people who are obese versus those who are of normal weight over a 5-year period have differential global and regional brain volumes.

    DESIGN: 

    Using voxel-based morphometry, contrasts were done between those who were recorded as being either obese or of normal weight over two time points in the 5 years prior to the brain scan. In a post-hoc preliminary analysis, we compared scores for obese and normal weight people who completed the trail-making task.

    SUBJECTS: 

    A total of 292 subjects were examined following exclusions (for example, owing to dementia, stroke and cortical infarcts) from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort with a body mass index of normal weight (<25 kg m−2) or obese (30 kg m−2).

    RESULTS: 

    People who were obese had significantly smaller total brain volumes and specifically, significantly reduced total gray matter (GM) volume (GMV) (with no difference in white matter or cerebrospinal fluid). Initial exploratory whole brain uncorrected analysis revealed that people who were obese had significantly smaller GMV in the bilateral supplementary motor area, bilateral dorsolateral prefrontal cortex (DLPFC), left inferior frontal gyrus and left postcentral gyrus. Secondary more stringent corrected analyses revealed a surviving cluster of GMV difference in the left DLPFC. Finally, post-hoc contrasts of scores on the trail-making task, which is linked to DLPFC function, revealed that obese people were significantly slower than those of normal weight.

    CONCLUSION: 

    These findings suggest that in comparison with normal weight, people who are obese have smaller GMV, particularly in the left DLPFC. Our results may provide evidence for a potential working memory mechanism for the cognitive suppression of appetite that may lower the risk of developing obesity in later life.

  • 41.
    Brooks, Samantha J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nilsson, Emil K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stein, Dan J
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e82707-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking.

    METHODS: 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF.

    RESULTS: The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes.

    CONCLUSIONS: The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.

  • 42.
    Brändström, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A single nucleotide polymorphism in the promoter region of the human gene for osteoprotegerin is related to vascular morphology and function2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, no 1, p. 13-17Article in journal (Refereed)
    Abstract [en]

    Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor receptor family, and has previously been shown to regulate bone mass by inhibiting osteoclast differentiation and activation. Recent evidence indicates that OPG also plays a role in the vascular system, since ablation of the OPG gene in mice results in calcification of the aorta and renal arteries, and association has been found between serum levels of OPG and cardiovascular mortality. This study presents a novel single nucleotide polymorphism, a T/C transition located 129 bp upstream the TATA-box of the human OPG gene, detected by sequence analysis. The OPG genotype was determined by restriction fragment length polymorphism in a cohort consisting of 59 healthy subjects. The intima-media thickness (IMT) in the common carotid artery and maximal post-ischemic forearm blood flow (FBF) were investigated. Subjects with the CC genotype showed a significantly increased IMT (p<0.05) and a concommitantly reduced maximal FBF (p<0.01) as compared to those with the T allele. Thus, our results show that the polymorphism in the promoter region of OPG is associated with both vascular morphology and function in apparently healthy subjects.

  • 43.
    Cai, Gui-Hong
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Theorell-Haglöw, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Elmståhl, Sölve
    Lund Univ, Skane Univ Hosp, Sweden CRC, Dept Hlth Sci,Div Geriatr Med, Malmo, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Both Weight at Age 20 and Weight Gain Have an Impact on Sleep Disturbances Later in Life: Results of the EpiHealth Study2018In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 41, no 1, article id zsx176Article in journal (Refereed)
    Abstract [en]

    Study Objectives: Obesity is often associated with impaired sleep, whereas the impact of body mass index (BMI) at younger age and previous weight gain on sleep problems remains unknown.

    Methods: The present study utilized data from the Swedish EpiHealth cohort study. A total of 15 845 participants (45-75 years) filled out an internet-based questionnaire. BMI was calculated from both measured data at study time and self-reported data at age 20 from the questionnaire.

    Results: Sleep-related symptoms were most common among obese individuals (BMI >30 kg/m(2)). An association between weight gain and sleep problems was found and those with a low BMI at age 20 were most vulnerable to weight gain when it came to risk of sleep problems. Among those who were underweight (BMI <18.5 kg/m(2)) at age 20, weight gain (kg/year) was associated with difficulties initiating sleep with an adjusted OR of 2.64 (95% CI: 1.51-4.62) after adjusting for age, sex, smoking, alcohol consumption, physical activity, education, and civil status. The corresponding adjusted OR's among those who had been normal weight (BMI 18.5-24.99) and overweight (BMI 25-29.99 kg/m(2)) at age 20 were 1.89 (1.47-2.45) and 1.02 (0.48-2.13), respectively. Also difficulties maintaining sleep and snoring were most strongly related to weight gain among those who were underweight at age 20 with decreasing odds with increasing BMI at that age.

    Conclusions: Sleep problems are related to weight gain and obesity. The impact of weight is most pronounced among those who had a low BMI when young.

  • 44.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Calamia, Michael
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    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, Molecular epidemiology.
    Kidney injury molecule (KIM)-1 is associated with insulin resistance: Results from two community-based studies of elderly individuals2014In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 103, no 3, p. 516-521Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Insulin resistance has been shown to be closely associated with glomerular filtration rate and urinary albumin/creatinine ratio, even prior to the development of diabetes. Urinary kidney injury molecule 1 (KIM-1) is a novel, highly specific marker of kidney tubular damage. The role of insulin resistance in the development of kidney tubular damage is not previously reported. Thus, we aimed to investigate the associations between insulin sensitivity (assessed by HOMA) and urinary KIM-1.

    DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Two community-based cohorts of elderly individuals were investigated: Prospective Investigation of the vasculature in Uppsala seniors (PIVUS, n=701; mean age 75 years, 52% women); and Uppsala Longitudinal Study of adult men (ULSAM, n=533; mean age 78 years).

    RESULTS: Lower insulin sensitivity was associated with higher urinary KIM-1 in both cohorts after adjustments for age, BMI, blood pressure, antihypertensive treatment, glomerular filtration rate, and urinary albumin-creatinine ratio (PIVUS: regression coefficient for 1-SD higher HOMA-IR 0.11, 95% CI 0.03-0.20, p=0.009, and ULSAM: 0.13, 95% CI 0.04-0.22, p=0.007). Results were similar in individuals without diabetes, with normal kidney function and normo-albuminuria.

    CONCLUSIONS: Our findings in elderly individuals support the notion that the interplay between an impaired glucose metabolism and renal tubular damage is evident even prior to the development of diabetes and overt kidney disease.

  • 45.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA.
    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.
    Carrero, Juan Jesus
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Feldreich, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Stenemo, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Use of Proteomics To Investigate Kidney Function Decline over 5 Years2017In: American Society of Nephrology. Clinical Journal, ISSN 1555-9041, E-ISSN 1555-905X, Vol. 12, no 8, p. 1226-1235Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Using a discovery/replication approach, we investigated associations between a multiplex panel of 80 circulating proteins associated with cardiovascular pathology or inflammation, and eGFR decline per year and CKD incidence.

    DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used two cohorts, the Prospective Investigation of the Vasculature in Uppsala Seniors Study (PIVUS; n=687, mean age of 70 years, 51% women) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=360 men, mean age of 78 years), with 5-year follow-up data on eGFR. There were 231 and 206 incident cases of CKD during follow-up in the PIVUS and ULSAM studies, respectively. Proteomic profiling of 80 proteins was assessed by a multiplex assay (proximity extension assay). The assay uses two antibodies for each protein and a PCR step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations.

    RESULTS: In the discovery cohort from the PIVUS Study, 28 plasma proteins were significantly associated with eGFR decline per year, taking into account the multiple testing. Twenty of these proteins were significantly associated with eGFR decline per year in the replication cohort from the ULSAM Study after adjustment for age, sex, cardiovascular risk factors, medications, and urinary albumin-to-creatinine ratio (in order of significance: TNF-related apoptosis-inducing ligand receptor 2*, CD40L receptor, TNF receptor 1*, placenta growth factor*, thrombomodulin*, urokinase plasminogen activator surface receptor*, growth/differentiation factor 15*, macrophage colony-stimulating factor 1, fatty acid-binding protein*, cathepsin D, resistin, kallikrein 11*, C-C motif chemokine 3, proteinase-activated receptor 1*, cathepsin L, chitinase 3-like protein 1, TNF receptor 2*, fibroblast growth factor 23*, monocyte chemotactic protein 1, and kallikrein 6). Moreover, 11 of the proteins predicted CKD incidence (marked with * above). No protein consistently predicted eGFR decline per year independently of baseline eGFR in both cohorts.

    CONCLUSIONS: Several circulating proteins involved in phosphate homeostasis, inflammation, apoptosis, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction were associated with worsening kidney function. Multiplex proteomics appears to be a promising way of discovering novel aspects of kidney disease pathology.

  • 46.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Juhlin, C Christofer
    Larsson, Tobias E
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    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.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lind, Lars
    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, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Soluble tumor necrosis factor receptor 1 (sTNFR1) is associated with increased total mortality due to cancer and cardiovascular causes: Findings from two community based cohorts of elderly2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 237, no 1, p. 236-242Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Experimental evidence support soluble receptors for tumor necrosis factor alpha as important mediators of the underlying pathology leading to cardiovascular disease and cancer. However, prospective data concerning the relation between circulating soluble tumor necrosis factor receptor-1 (sTNFR1) and mortality in humans are lacking. We aimed to explore and validate the association between sTNFR1 and mortality, and to explore the influence of other established risk factors for mortality, including other inflammatory markers.

    METHODS: The association between serum sTNFR1and the risk for mortality was investigated in two community-based cohorts of elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n = 1005, mean age 70 years, median follow-up 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 775, mean age 77 years, median follow-up 8.1 years).

    RESULTS: In total, 101 participants in PIVUS and 274 in ULSAM died during follow-up. In multivariable Cox regression models adjusted for inflammation, lifestyle and established cardiovascular risk factors, one standard deviation (SD) higher sTNFR1 was associated with a hazard ratio (HR) for mortality of 1.37, 95% confidence interval (CI) 1.17-1.60, in PIVUS and HR 1.22, 95% CI 1.10-1.37 in ULSAM. Moreover, circulatingsTNFR1 was associated with cardiovascular mortality (HR per SD of sTNFR1, 1.24, 95% CI 1.07-1.44) and cancer mortality (HR per SD of sTNFR1, 1.32, 95% CI 1.11-1.57) in the ULSAM cohort. High levels of sTNFR1 identified individuals with increased risk of mortality among those with high as well as low levels of systemic inflammation.

    CONCLUSIONS: An association between circulating sTNFR1 and an increased risk for mortality was found and validated in two independent community-based cohorts. The future clinical role of sTNFR1 to identify high risk patients for adverse outcomes and mortality has yet to be determined.

  • 47.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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.
    Larsson, Tobias E
    Bottai, Matteo
    Sundström, 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.
    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.
    Urinary Kidney Injury Molecule-1 and the Risk of Cardiovascular Mortality in Elderly Men2014In: Clinical journal of the American Society of Nephrology : CJASN, ISSN 1555-905X, Vol. 9, no 8, p. 1393-1401Article in journal (Refereed)
    Abstract [en]

    Background and objectives

    Kidney injury molecule-1 (KIM-1) has been suggested as a clinically relevant highly specific biomarker of acute kidney tubular damage. However, community-based data on the association between urinary levels of KIM-1 and the risk for cardiovascular mortality are lacking. This study aimed to investigate the association between urinary KIM-1 and cardiovascular mortality.

    Design, setting, participants, & measurements

    This was a prospective study, using the community-based Uppsala Longitudinal Study of Adult Men (N=590; mean age 77 years; baseline period, 1997–2001; median follow-up 8.1 years; end of follow-up, 2008).

    Results

    During follow-up, 89 participants died of cardiovascular causes (incidence rate, 2.07 per 100 person-years at risk). Models were adjusted for cardiovascular risk factors (age, systolic BP, diabetes, smoking, body mass index, total cholesterol, HDL cholesterol, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, and history of cardiovascular disease) and for markers of kidney dysfunction and damage (cystatin C–based eGFR and urinary albumin/creatinine ratio). Higher urinary KIM-1/creatinine (from 24-hour urine collections) was associated with a higher risk for cardiovascular mortality (hazard ratio per SD increase, 1.27; 95% confidence interval [95% CI], 1.05 to 1.54; P=0.01). Participants with a combination of high KIM-1/creatinine (upper quintile, ≥175 ng/mmol), low eGFR (≤60 ml/min per 1.73 m2), and microalbuminuria/macroalbuminuria (albumin/creatinine ratio≥3 g/mol) had a >8-fold increased risk compared with participants with low KIM-1/creatinine (<175 ng/mmol), normal eGFR (>60 ml/min per 1.73 m2), and normoalbuminuria (albumin/creatinine ratio<3 g/mol) (hazard ratio, 8.56; 95% CI, 4.17 to 17.56; P<0.001).

    Conclusions

    These findings suggest that higher urinary KIM-1 may predispose to a higher risk of cardiovascular mortality independently of established cardiovascular risk factors, eGFR, and albuminuria. Additional studies are needed to further assess the utility of measuring KIM-1 in the clinical setting.

  • 48.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Erik
    Larsson, Tobias E
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Urinary kidney injury molecule 1 and incidence of heart failure in elderly men2013In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 15, no 4, p. 441-446Article in journal (Refereed)
    Abstract [en]

    AIMS:

    There is growing recognition of the clinical importance of cardiorenal syndrome-the bidirectional interplay between kidney and cardiac dysfunction. Yet, the role of kidney tubular damage in the development of heart failure is less studied. The objective of this study was to investigate whether urinary kidney injury molecule (KIM)-1, a specific marker of tubular damage, predisposes to an increased heart failure risk.

    METHODS AND RESULTS:

    This was a community-based cohort study [Uppsala Longitudinal study of Adult Men (ULSAM)] of 565, 77-year-old men free from heart failure at baseline. Heart failure hospitalizations were used as outcome. During follow-up (median 8.0 years), 73 participants were hospitalized for heart failure. In models adjusted for cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, LDL/HDL ratio, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, LV hypertrophy, and prevalent cardiovascular disease) and markers of kidney dysfunction and damage [cystatin C-based glomerular filtration rate (GFR) and urinary albumin/creatinine ratio], a higher urinary KIM-1/creatinine ratio was associated with higher risk for heart failure (hazard ratio upper vs. lower tertile, 1.81; 95% confidence interval 1.01-3.29; P < 0.05). Participants with a combination of low GFR (<60 mL/min/1.72 m(2)) and high KIM-1/creatinine (>128 ng/mmol) had a 3-fold increase in heart failure risk compared with participants with normal GFR and KIM-1 (P < 0.001).

    CONCLUSION:

    Our findings suggest that kidney tubular damage predisposes to an increased risk for heart failure in the community. Further studies are needed to clarify the causal role of KIM-1 in the development of heart failure, and to evaluate the clinical utility of urinary KIM-1 measurements.

  • 49.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Larsson, Tobias E
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    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, Molecular epidemiology.
    Soluble TNF Receptors and Kidney Dysfunction in the Elderly2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 6, p. 1313-1320Article in journal (Refereed)
    Abstract [en]

    The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=-0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.

  • 50.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Larsson, Tobias E.
    Carrero, Juan-Jesús
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. gSchool of Health and Social Studies, Dalarna University, Falun , Sweden.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Soluble Tumor Necrosis Factor Receptor 1 Is Associated with Glomerular Filtration Rate Progression and Incidence of Chronic Kidney Disease in Two Community-Based Cohorts of Elderly Individuals2015In: Cardiorenal Medicine, ISSN 1664-3828, Vol. 5, no 4, p. 278-288Article in journal (Refereed)
    Abstract [en]

    Objective: We aimed to explore and validate the longitudinal associations between soluble tumor necrosis factor receptor 1 (sTNFR1), glomerular filtration rate (GFR) progression, and chronic kidney disease (CKD) incidence in two independent community-based cohorts of elderly individuals with prespecified subgroup analyses in individuals without prevalent diabetes. Research Design and Methods: Two community-based cohorts of elderly individuals were used with 5-year follow-up data on estimated GFR: the Uppsala Longitudinal Study of Adult Men (ULSAM; n = 437 men; mean age: 78 years) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; n = 703; mean age: 70 years; 51% women). GFR categories were defined as >= 60, 30-60, and = 60 ml/min/1.73 m(2) at baseline, higher sTNFRs were associated with incident CKD after 5 years in both cohorts [ULSAM: OR per SD increase 1.49 (95% CI 1.16-1.9) and PIVUS: OR 1.84 (95% CI 1.50-2.26)]. Associations were similar in individuals without diabetes. Conclusions: Higher circulating sTNFR1 independently predicts the progression to a worse GFR category and CKD incidence in elderly individuals even in the absence of diabetes. Further studies are warranted to investigate the underlying mechanisms, and to evaluate the clinical relevance of our findings.

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