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- Forsberg, Lars A., et al.
(författare)
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Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:6, s. 624-628
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Tidskriftsartikel (refereegranskat)abstract
- Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
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- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- 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. © 2014 Nature America, Inc.
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| 5. |
- Do, Ron, et al.
(författare)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Tidskriftsartikel (refereegranskat)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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- Hagström, Emil, et al.
(författare)
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Plasma parathyroid hormone and risk of congestive heart failure in the community
- 2010
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 12:11, s. 1186-1192
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Tidskriftsartikel (refereegranskat)abstract
- In experimental studies parathyroid hormone (PTH) has been associated with underlying causes of heart failure (HF) such as atherosclerosis, left ventricular hypertrophy, and myocardial fibrosis. Individuals with increased levels of PTH, such as primary or secondary hyperparathyroidism patients, have increased risk of ischaemic heart disease and HF. Moreover, increasing PTH is associated with worse prognosis in patients with overt HF. However, the association between PTH and the development HF in the community has not been reported. In a prospective, community-based study of 864 elderly men without HF or valvular disease at baseline (mean age 71 years, the ULSAM study) the association between plasma (P)-PTH and HF hospitalization was investigated adjusted for established HF risk factors (myocardial infarction, hypertension, diabetes, electrocardiographic left ventricular hypertrophy, smoking, and hypercholesterolaemia) and variables reflecting mineral metabolism (S-calcium, S-phosphate, P-vitamin D, S-albumin, dietary calcium and vitamin D intake, physical activity, glomerular filtration rate, and blood draw season). During follow-up (median 8 years), 75 individuals were hospitalized due to HF. In multivariable Cox-regression analyses, higher P-PTH was associated with increased HF hospitalization (hazard ratio for 1-SD increase of PTH, 1.41, 95% CI 1.12-1.77, P = 0.003). Parathyroid hormone also predicted hospitalization in participants without apparent ischaemic HF and in participants with normal P-PTH. In a large community-based sample of elderly men, PTH predicted HF hospitalizations, also after accounting for established risk factors and mineral metabolism variables. Our data suggest a role for PTH in the development of HF even in the absence of overt hyperparathyroidism.
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| 7. |
- Hagström, Emil, et al.
(författare)
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Plasma-parathyroid hormone is associated with subclinical and clinical atherosclerotic disease in 2 community-based cohorts
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 34:7, s. 1567-1579
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cardiovascular risk factors have different impact on different arterial territories. Diseases with elevated circulating parathyroid hormone (PTH) such as primary hyperparathyroidism and chronic renal failure have been shown to be associated with an increased risk of cardiovascular disease, predominantly heart or cerebrovascular diseases. However, data on the associations between circulating PTH and peripheral atherosclerosis are limited.APPROACH AND RESULTS: Two prospective, community-based studies were used. In 306 men and women, who were 70 years old, from the Prospective investigation of the vasculature in Uppsala seniors (PIVUS) study, cross-sectional relations between PTH and atherosclerotic burden assessed by whole-body magnetic resonance angiography were investigated. In 998 men, who were 71 years old, from the Uppsala longitudinal study of adult men (ULSAM) study, the association between PTH concentration and risk of subsequent nonfatal atherosclerotic disease (excluding coronary or cerebrovascular disease) was investigated. Adjusting for established vascular risk factors, PTH was associated with burden of atherosclerosis (increase in total atherosclerotic score per SD PTH increase: 0.04, 0.003-0.08; P=0.03) in the PIVUS study. During follow-up in the ULSAM study (median 16.7 years), 89 men were diagnosed with nonfatal atherosclerotic disease. In Cox-regression analyses adjusting for established vascular risk factors and mineral metabolism, higher PTH was associated with an increased risk of nonfatal atherosclerotic disease (hazard ratio for 1 SD increase of PTH: 1.55, 1.33-1.88; P<0.0001). Results were similar when including fatal atherosclerotic disease in the outcome.CONCLUSIONS: In 2 independent community-based cohorts, PTH was associated to the degree of atherosclerosis and risk of clinically overt atherosclerotic disease, respectively. Our data confirm and extend previous studies supporting a role for PTH in the development of atherosclerotic disease.
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| 8. |
- Kumar, Jitender, et al.
(författare)
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Influence of persistent organic pollutants on oxidative stress in population-based samples
- 2014
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 114, s. 303-309
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Tidskriftsartikel (refereegranskat)abstract
- Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and BC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (beta = 0.94; P = 2.9 * 10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: beta = 0.01; P = 6.0 *10(-7); GSSG/GSH: beta = 0.002; P = 9.7 * 10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress. (C) 2014 Elsevier Ltd. All rights reserved.
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| 9. |
- Kumar, Jitender, et al.
(författare)
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Influence of persistent organic pollutants on the complement system in a population-based human sample
- 2014
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 71, s. 94-100
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Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent organic pollutants (POPS) are toxic compounds generated through various industrial activities and have adverse effects on human health. Studies performed in cell cultures and animals have revealed that POPs can alter immune-system functioning. The complement system is part of innate immune system that helps to clear pathogens from the body. We performed a large-scale population-based study to find out associations between summary measures of different POPs and different complement system markers.Methods: In this cross-sectional study, 16 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, octachloro-p-dibenzodioxin, and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) were analyzed for their association with levels of protein complement 3 (C3), 3a (C3a), 4 (C4) and C3a/C3 ratio. A total of 992 individuals (all aged 70 years, 50% females) were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. Regression analysis adjusting for a variety of confounders was performed to study the associations of different POP exposures (total toxic equivalency value or TEQ and sum of 16 PCBs) with protein complements.Results: The TEQ values were found to be positively associated with C3a (beta = 0.07, 95% CI = 0.017-0.131, p = 0.01) and C3a/C3 ratio (beta = 0.07, 95% Cl = 0.015-0.126, p = 0.01) taking possible confounders into account. The association observed was mainly driven by PCB-126.Conclusion: In this study involving 992 elderly individuals from the general population, we showed that POPs, mainly PCB-126, were associated with levels of complement system markers indicating that the association of these toxic compounds with downstream disease could be mediated by activation of immune system. (C) 2014 Elsevier Ltd. All rights reserved.
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| 10. |
- Kumar, Jitender, et al.
(författare)
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Persistent Organic Pollutants and Inflammatory Markers in a Cross-Sectional Study of Elderly Swedish People : The PIVUS Cohort
- 2014
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Ingår i: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Science. - 0091-6765 .- 1552-9924. ; 122:9, s. 977-983
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Persistent organic pollutants (POPs) are compounds that are generated through various industrial activities and released in the surrounding environment. Different animal studies have shown effects of different POPs on various inflammatory markers.OBJECTIVE: Because very few studies have been conducted in humans, we assessed the associations between different POPs and inflammatory markers in a large population-based sample of elderly men and women (all 70 years of age) from Sweden.METHODS: This cross-sectional study investigated the concentrations of several polychlorinated biphenyls (PCBs), organochlorine pesticides, polychlorinated dibenzo-p-dioxin, and brominated diphenyl ether congeners and their association with a number of inflammatory markers [vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, C-reactive protein (CRP), total leucocyte count, tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and interleukin 6 (IL-6)] in 992 individuals. These individuals were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. We used a total toxic equivalency (TEQ) value that measures toxicological effects with the relative potencies of various POPs.RESULTS: Following adjustment for potential confounders, the TEQ value (driven mainly by PCB-126) was significantly associated with levels of ICAM-1 (p < 10(-5)). A similar trend was also observed between sum of PCBs and VCAM-1 (p < 0.001). No significant associations were observed between levels of POPs and other inflammatory markers.CONCLUSIONS: TEQ values were associated with levels of ICAM-1, to a lesser degree also with VCAM-1, but not with CRP and several other inflammatory markers. These findings suggest an activation of vascular adhesion molecules by POPs, and particularly by PCB-126.
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