Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Abstract

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

“…While we were unable to formally demonstrate an interaction between these genes (P = 0.07) we consider this to be a biologically relevant interaction that warrants further investigation (cf below). In support of our findings, a recent genome wide association study, performed to identify new loci that influence lipid concentrations (Willer et al, 2008), failed to identify the HMGCR gene as a potential modifier of cholesterol concentrations using Affymetrix and Illumina arrays that each contained the polymorphism of interest (rs3761740).…”

Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

“…Several GWAS have associated the encoding locus SORT1 at 1p13.3 with plasma levels of cholesterol and risk of myocardial infarction in humans, implicating sortilin in systemic cholesterol homeostasis [34][35][36][37] . Subsequently, a SNP at 1p13.3 was identified that represents a binding site for the transcription factor C/EBP.…”

Genetic architecture of circulating lipid levels

“…[1][2][3][4] A number of genome-wide association studies (GWASs) successfully identified multiple genes influencing circulating lipid levels. [5][6][7][8][9][10][11][12] There are currently over 100 established loci that include both common variants with relatively small effects as well as a considerable number of rare variants with large effects. 13 Despite these successes, a substantial proportion of the heritability of each trait remains unexplained, suggesting that many determinants have yet to be identified.…”