Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.

BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD

Mendelian randomization of blood lipids for coronary heart disease

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain

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 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 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 ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). 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

The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

BACKGROUND: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. METHODS AND FINDINGS: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n  =  198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p  =  0.001). CONCLUSIONS: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

The arcOGEN Consortium should be listed as an author of this article. They contributed to the genome-wide association study results presented in this work. They should be listed in the author byline at position 292 and affiliated with The Arthritis Research UK Osteoarthritis Genetics Consortium. They should also be included in the footnote designating consortia which is underneath the author affiliation list in the PDF version of the article, and in the S2 Text. Please view the correct S2 Text below, containing correct consortia members. S2 Text. Consortia members and extended acknowledgments. https://doi.org/10.1371/journal.pgen.1006166.s001 (DOCX) [This corrects the article DOI: 10.1371/journal.pgen.1005378.]

Sex-stratified genoSex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits