Biological, clinical and population relevance of 95 loci for blood lipids

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10−8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. Lipid concentration in the blood is a major risk factor for coronary artery disease, and one that can be targeted for therapeutic intervention. A genome-wide association study (GWAS) in more than 100,000 individuals of European ancestry has been used to identify 95 genetic variants linked to plasma lipids. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and novel loci that contribute to normal variation in lipid traits and to extreme lipid phenotypes. One locus identified in the study as being associated with both plasma low-density lipoprotein cholesterol and coronary artery disease forms the focus of a second paper in this issue. The locus, on chromosome 1p13, is shown to create a binding site for C/EBP transcription factors and to alter SORT1 gene expression in the liver. Modulating Sort1 levels in the mouse liver alters plasma lipoprotein levels, potentially explaining why variation at this locus is associated with heart disease. This finding identifies the sortilin pathway as a possible target for therapeutic intervention and illustrates how GWAS results can be used as a production line for drug targets. Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.