| 21. |
- Holmes, Michael V., et al.
(författare)
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Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
- 2013
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
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Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
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| 22. |
- Jannasch, Franziska, et al.
(författare)
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Associations between exploratory dietary patterns and incident type 2 diabetes : a federated meta-analysis of individual participant data from 25 cohort studies.
- 2022
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Ingår i: European Journal of Nutrition. - : Springer Nature. - 1436-6207 .- 1436-6215. ; 61:7, s. 3649-3667
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: In several studies, exploratory dietary patterns (DP), derived by principal component analysis, were inversely or positively associated with incident type 2 diabetes (T2D). However, findings remained study-specific, inconsistent and rarely replicated. This study aimed to investigate the associations between DPs and T2D in multiple cohorts across the world.METHODS: This federated meta-analysis of individual participant data was based on 25 prospective cohort studies from 5 continents including a total of 390,664 participants with a follow-up for T2D (3.8-25.0 years). After data harmonization across cohorts we evaluated 15 previously identified T2D-related DPs for association with incident T2D estimating pooled incidence rate ratios (IRR) and confidence intervals (CI) by Piecewise Poisson regression and random-effects meta-analysis.RESULTS: 29,386 participants developed T2D during follow-up. Five DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, were associated with higher incidence of T2D. The strongest association was observed for a DP comprising these food groups besides others (IRRpooled per 1 SD = 1.104, 95% CI 1.059-1.151). Although heterogeneity was present (I2 = 85%), IRR exceeded 1 in 18 of the 20 meta-analyzed studies. Original DPs associated with lower T2D risk were not confirmed. Instead, a healthy DP (HDP1) was associated with higher T2D risk (IRRpooled per 1 SD = 1.057, 95% CI 1.027-1.088).CONCLUSION: Our findings from various cohorts revealed positive associations for several DPs, characterized by higher intake of red meat, processed meat, French fries and refined grains, adding to the evidence-base that links DPs to higher T2D risk. However, no inverse DP-T2D associations were confirmed.
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| 23. |
- Johnson, Toby, et al.
(författare)
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Blood Pressure Loci Identified with a Gene-Centric Array.
- 2011
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 89:6, s. 688-700
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Tidskriftsartikel (refereegranskat)abstract
- Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56× 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56× 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
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| 24. |
- Khan, Tauseef A., et al.
(författare)
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Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke : Systematic review and meta-analysis of 14 015 stroke cases and pooled analysis of primary biomarker data from up to 60 883 individuals
- 2013
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 42:2, s. 475-492
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Tidskriftsartikel (refereegranskat)abstract
- Background At the APOE gene, encoding apolipoprotein E, genotypes of the epsilon 2/epsilon 3/epsilon 4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. Methods We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). Results The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for epsilon 2/epsilon 2; 0.85 (95% CrI: 0.78-0.92) for epsilon 2/epsilon 3; 1.05 (95% CrI: 0.89-1.24) for epsilon 2/epsilon 4; 1.05 (95% CrI: 0.99-1.12) for epsilon 3/epsilon 4; and 1.12 (95% CrI: 0.94-1.33) for epsilon 4/epsilon 4 using the epsilon 3/epsilon 3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 x 10(-152)), apolipoprotein B (P-trend: 8.7 x 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 x 10(-26)) and HDL-C (P-trend: 1.6 x 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. Conclusions In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE epsilon 2/epsilon 2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
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| 25. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 26. |
- Lee, Crystal, et al.
(författare)
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Association of anthropometry and weight change with risk of dementia and its major subtypes: a meta-analysis consisting 2.8 million adults with 57,294 cases of dementia
- 2020
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Ingår i: Obesity Reviews. - : Wiley. - 1467-7881 .- 1467-789X. ; 21:4
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Tidskriftsartikel (refereegranskat)abstract
- Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5–22.4 kg/m2), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5–24.9 kg/m2) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had non-significant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change and dementia is complex and exhibits nonlinear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.
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| 27. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 28. |
- Melchior, Maria, et al.
(författare)
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Does sickness absence due to psychiatric disorder predict cause-specific mortality? A 16-year follow-up of the GAZEL occupational cohort study.
- 2010
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 172:6, s. 700-7
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Tidskriftsartikel (refereegranskat)abstract
- Mental disorders are a frequent cause of morbidity and sickness absence in working populations; however, the status of psychiatric sickness absence as a predictor of mortality is not established. The authors tested the hypothesis that psychiatric sickness absence predicts mortality from leading medical causes. Data were derived from the French GAZEL cohort study (n = 19,962). Physician-certified sickness absence records were extracted from administrative files (1990-1992) and were linked to mortality data from France's national registry of mortality (1993-2008, mean follow-up: 15.5 years). Analyses were conducted by using Cox regression models. Compared with workers with no sickness absence, those absent due to psychiatric disorder were at increased risk of cause-specific mortality (hazard ratios (HRs) adjusted for age, gender, occupational grade, other sickness absence-suicide: 6.01, 95% confidence interval (CI): 3.07, 11.75; cardiovascular disease: 1.84, 95% CI: 1.10, 3.08; and smoking-related cancer: 1.65, 95% CI: 1.07, 2.53). After full adjustment, the excess risk of suicide remained significant (HR = 5.13, 95% CI: 2.60, 10.13) but failed to reach statistical significance for fatal cardiovascular disease (HR = 1.59, 95% CI: 0.95, 2.66) and smoking-related cancer (HR = 1.31, 95% CI: 0.85, 2.03). Psychiatric sickness absence records could help identify individuals at risk of premature mortality and serve to monitor workers' health.
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| 29. |
- Melchior, Maria, et al.
(författare)
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Using sickness absence records to predict future depression in a working population : prospective findings from the GAZEL cohort.
- 2009
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Ingår i: American journal of public health. - 1541-0048. ; 99:8, s. 1417-22
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We tested the hypothesis that sickness absence from work predicts workers' risk of later depression. METHODS: Study participants (n = 7391) belonged to the French GAZEL cohort of employees of the national gas and electricity company. Sickness absence data (1996-1999) were obtained from company records. Participants' depression in 1996 and 1999 was assessed with the Center for Epidemiologic Studies-Depression (CES-D) scale. The analyses were controlled for baseline age, gender, marital status, occupational grade, tobacco smoking status, alcohol consumption, subthreshold depressive symptoms, and work stress. RESULTS: Among workers who were free of depression in 1996, 13% had depression in 1999. Compared with workers with no sickness absence during the study period, those with sickness absence were more likely to be depressed at follow-up (for 1 period of sickness absence, fully adjusted odds ratio [OR] = 1.53, 95% confidence interval [CI] = 1.28, 1.82; for 2 or more periods, fully adjusted OR = 1.95, 95% CI = 1.61, 2.36). Future depression was predicted both by psychiatric and nonpsychiatric sickness absence (fully adjusted OR = 3.79 [95% CI = 2.81, 5.10] and 1.41 [95% CI = 1.21, 1.65], respectively). CONCLUSIONS: Sickness absence records may help identify workers vulnerable to future depression.
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| 30. |
- Nwaru, Chioma A., et al.
(författare)
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Sickness absence in a re-employment program as a predictor of labor market attachment among long-term unemployed individuals : A 6-year cohort study in Finland
- 2018
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Ingår i: Scandinavian Journal of Work, Environment and Health. - : SCANDINAVIAN JOURNAL WORK ENVIRONMENT & HEALTH. - 0355-3140 .- 1795-990X. ; 44:5, s. 496-502
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Tidskriftsartikel (refereegranskat)abstract
- Objectives We examined whether sickness absence during participation in a state subsidized re-employment program among long-term unemployed people was associated with subsequent labor market attachment. Methods We linked 18 944 long-term unemployed participants (aged 18-60 years) of a six-month subsidized re-employment program in Finland to their records of sickness absence during the program and labor market status after the program. We used the latent class growth model to identify labor market attachment trajectories over a six-year follow-up period and multinomial logistic regression to investigate the association between sickness absence and labor market attachment trajectories. Results We identified four labor market attachment trajectories: "strengthening", (77%), "delayed" (6%), "leavers" (10%), and "non-attached" (7%). Sickness absence was associated with an increased risk of belonging to the leavers and non-attached trajectories. Having > 30 days of sickness absence during the six-month re-employment program increased the risk for belonging to the future non-attached trajectory in all age groups, but in particular for those aged 30-44 [ odds ratio (OR) 7.35, 95% confidence interval (CI) 4.85-11.14] and 18-29 years (OR 5.38, 95% CI 3.76-7.69). At these ages, having fewer than 30 days sickness absences was also associated with an elevated risk of belonging to the non-attached trajectory, while this risk was lower for those aged 45-60. Conclusions Sickness absence during participation in a subsidized re-employment program increased the risk for poor labor market attachment during the subsequent six years. The risk was particularly high among younger participants with > 30 days of sickness absence.
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