7 research outputs found
A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8)). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19) for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8), n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6), n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3), n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (Pâ€5Ă10â8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of Pâ€0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2Ă10â19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9Ă10â8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5Ă10â6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2Ă10â3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
Background
Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.
Methods
In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125â222 participants. We also compared the frequency of Asp358Ala in 51â441 patients with coronary heart disease and in 136â226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.
Findings
The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele â„0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4â38·2) and of interleukin 6 by 14·6% (10·7â18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9â9·1) and of fibrinogen by 1·0% (0·7â1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8â5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.
Interpretation
Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
Funding
British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation
Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 à 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this
association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent
of non-genetic confounding, and are unmodifi ed by disease processes, mendelian random isation can be used to test
the hypothesis that the association of a plasma biomarker with disease is causal.
Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide
polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies
(20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of
14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of
myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs
exclusively associated with LDL cholesterol.
Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher,
p=8Ă10â
ÂčÂł) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers.
This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio
[OR] 0·87, 95% CI 0·84â0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial
infarction (OR 0·99, 95% CI 0·88â1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL
cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58â0·66). However, a 1 SD
increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93,
95% CI 0·68â1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in
LDL cholesterol associated with OR 1·54, 95% CI 1·45â1·63) was concordant with that from genetic score (OR 2·13,
95% CI 1·69â2·69, p=2Ă10â
Âčâ°).
Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial
infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into
reductions in risk of myocardial infarction.
Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the
German Federal Ministry of Education and Research
Common variants at 10 genomic loci influence hemoglobin Aâ(C) levels via glycemic and nonglycemic pathways.
Glycated hemoglobin (HbAâ(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbAâ(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbAâ(c) levels
RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies
Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years). Conclusions: High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies. © 2011 Herder et al
Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (Pâ=â4.5Ă10(-8)-1.2Ă10(-43)). Using a novel method to combine data across ethnicities (Nâ=â4,232 African Americans, Nâ=â1,776 Asians, and Nâ=â29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3Ă10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (pâ=â4.3Ă10(-3), nâ=â22,044), increased triglycerides (pâ=â2.6Ă10(-14), nâ=â93,440), increased waist-to-hip ratio (pâ=â1.8Ă10(-5), nâ=â77,167), increased glucose two hours post oral glucose tolerance testing (pâ=â4.4Ă10(-3), nâ=â15,234), increased fasting insulin (pâ=â0.015, nâ=â48,238), but with lower in HDL-cholesterol concentrations (pâ=â4.5Ă10(-13), nâ=â96,748) and decreased BMI (pâ=â1.4Ă10(-4), nâ=â121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance