| 1. |
- Nilsson, Emma A, et al.
(författare)
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Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:9, s. 2962-2976
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Tidskriftsartikel (refereegranskat)abstract
- Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
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| 2. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Hansson, Jenny, et al.
(författare)
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Use of snus and acute myocardial infarction: pooled analysis of eight prospective observational studies
- 2012
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 27:10, s. 771-779
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Tidskriftsartikel (refereegranskat)abstract
- The use of snus (also referred to as Scandinavian or Swedish moist smokeless tobacco), which is common in Sweden and increasing elsewhere, is receiving increasing attention since considered a tobacco smoke "potential reduction exposure product". Snus delivers a high dose of nicotine with possible hemodynamic effects, but its impact on cardiovascular morbidity and mortality is uncertain. The aim of this study was to investigate whether snus use is associated with risk of and survival after acute myocardial infarction (AMI). Data from eight prospective cohort studies set in Sweden was pooled and reanalysed. The relative risk of first time AMI and 28-day case-fatality was calculated for 130,361 men who never smoked. During 2,262,333 person-years of follow-up, 3,390 incident events of AMI were identified. Current snus use was not associated with risk of AMI (pooled multivariable hazard ratio 1.04, 95 % confidence interval 0.93 to 1.17). The short-term case fatality rate appeared increased in snus users (odds ratio 1.28, 95 % confidence interval 0.99 to 1.68). This study does not support any association between use of snus and development of AMI. Hence, toxic components other than nicotine appear implicated in the pathophysiology of smoking related ischemic heart disease. Case fatality after AMI is seemingly increased among snus users, but this relationship may be due to confounding by socioeconomic or life style factors.
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| 4. |
- Andel, Ross, et al.
(författare)
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Work-related exposure to extremely low-frequency magnetic fields and dementia: results from the population-based study of dementia in Swedish twins.
- 2010
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1758-535X .- 1079-5006. ; 65:11, s. 1220-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We examined the association between extremely low-frequency magnetic fields (EMF) and the risk of dementia and Alzheimer's disease using all 9,508 individuals from the Study of Dementia in Swedish Twins (HARMONY) with valid occupational and diagnostic data. METHODS: Dementia diagnoses were based on telephone screening followed by in-person clinical workup. Main lifetime occupation was coded according to an established EMF exposure matrix. Covariates were age, gender, education, vascular risk factors, and complexity of work. Based on previous research, data were also analyzed separately for cases with disease onset by age 75 years versus later, men versus women, and those with manual versus nonmanual main occupation. We used generalized estimating equations with the entire sample (to adjust for the inclusion of complete twin pairs) and conditional logistic regression with complete twin pairs only. RESULTS: Level of EMF exposure was not significantly associated with dementia or Alzheimer's disease. However, in stratified analyses, medium and high levels of EMF exposure were associated with increased dementia risk compared with low level in cases with onset by age 75 years (odds ratio: 1.94, 95% confidence interval: 1.07-3.65 for medium, odds ratio: 2.01, 95% confidence interval: 1.10-3.65 for high) and in participants with manual occupations (odds ratio: 1.81, 95% confidence interval: 1.06-3.09 for medium, odds ratio: 1.75, 95% confidence interval: 1.00-3.05 for high). Results with 42 twin pairs discordant for dementia did not reach statistical significance. CONCLUSIONS: Occupational EMF exposure appears relevant primarily to dementia with an earlier onset and among former manual workers.
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| 5. |
- Baliakas, Panagiotis, et al.
(författare)
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Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study
- 2014
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Ingår i: The Lancet Haematology. - 2352-3026. ; 1:2, s. 74-84
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Tidskriftsartikel (refereegranskat)abstract
- Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome of our analysis was time to first treatment, defined as the time between diagnosis and date of first treatment. Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 major subsets. Stereotyped subsets showed significant differences in terms of age, sex, disease burden at diagnosis, CD38 expression, and cytogenetic aberrations of prognostic significance. Patients within a specific subset generally followed the same clinical course, whereas patients in different stereotyped subsets-despite having the same immunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showed substantially different times to first treatment. By integrating B-cell receptor immunoglobulin stereotypy (for subsets 1, 2, and 4) into the well established Dohner cytogenetic prognostic model, we showed these, which collectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). Interpretation The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Dohner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.
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| 6. |
- 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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| 7. |
- Fuks, Kateryna B., et al.
(författare)
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Arterial blood pressure and long-term exposure to traffic-related air pollution : an analysis in the European Study of Cohorts for Air Pollution Effects (ESCAPE)
- 2014
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Ingår i: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Sciences (NIEHS). - 0091-6765 .- 1552-9924. ; 122:9, s. 896-905
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Long-term exposure to air pollution is hypothesized to elevate arterial blood pressure (BP). The existing evidence is scarce and country-specific. OBJECTIVES: We investigated the cross-sectional association of long-term traffic-related air pollution with BP and prevalent hypertension in European populations. METHODS: Fifteen population-based cohorts, participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE), were analysed. Residential exposure to particulate matter and nitrogen oxides was modelled with land use regression using a uniform protocol. Traffic exposure was assessed with traffic indicator variables. We analysed systolic and diastolic BP in participants medicated and non-medicated with BP lowering medication (BPLM) separately, adjusting for personal and area-level risk factors and environmental noise. Prevalent hypertension was defined as ≥ 140 mmHg systolic, or ≥ 90 mmHg diastolic BP, or intake of BPLM. We combined cohort-specific results using random-effects meta-analysis. RESULTS: In the main meta-analysis of 113,926 participants, traffic load on major roads within 100 m of the residence was associated with increased systolic and diastolic BP in non-medicated participants (0.35 mmHg [95% CI: 0.02-0.68] and 0.22 mmHg [95% CI: 0.04-0.40] per 4,000,000 vehicles × m/day, respectively). The estimated odds ratio for prevalent hypertension was 1.05 [95% CI: 0.99-1.11] per 4,000,000 vehicles × m/day. Modelled air pollutants and BP were not clearly associated. CONCLUSIONS: In this first comprehensive meta-analysis of European population-based cohorts we observed a weak positive association of high residential traffic exposure with BP in non-medicated participants, and an elevated OR for prevalent hypertension. The relationship of modelled air pollutants with BP was inconsistent.
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| 8. |
- Hallberg, Jenny, et al.
(författare)
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Genetic and environmental influence on lung function impairment in Swedish twins
- 2010
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods: The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results: Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were 10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion: Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.
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| 9. |
- Helgadottir, Anna, et al.
(författare)
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Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism
- 2012
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:8, s. 722-729
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (ne = 4,572); venous thromboembolism (ne = 4,607); intracranial aneurysm (ne = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 X 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 x 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 x 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. (J Am Coll Cardiol 2012; 60: 722-9) (C) 2012 by the American College of Cardiology Foundation
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| 10. |
- Hergens, Maria-Pia, et al.
(författare)
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Use of Scandinavian Moist Smokeless Tobacco (Snus) and the Risk of Atrial Fibrillation
- 2014
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Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 25:6, s. 872-876
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Snus is a smokeless tobacco product, widely used among Swedish men and increasingly so elsewhere. There is debate as to whether snus is an acceptable "harm-reduction" tobacco product. Since snus use delivers a dose of nicotine equivalent to cigarettes, and has been implicated in cardiac arrhythmia because of associations with sudden cardiovascular death, a relation with atrial fibrillation is plausible and important to investigate.METHODS:: To assess the relation between use of snus and risk of atrial fibrillation, we carried out a pooled analysis of 7 prospective Swedish cohort studies. In total, 274,882 men, recruited between 1978 and 2004, were followed via the National Patient Register for atrial fibrillation. Primary analyses were restricted to 127,907 never-smokers. Relative risks were estimated using Cox proportional hazard regression.RESULTS:: The prevalence of snus use was 25% among never-smokers. During follow-up, 3,069 cases of atrial fibrillation were identified. The pooled relative risk of atrial fibrillation was 1.07 (95% confidence interval = 0.97-1.19) in current snus users, compared with nonusers.CONCLUSION:: Findings from this large national pooling project indicate that snus use is unlikely to confer any important increase in risk of atrial fibrillation.
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