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

Abstract

Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) 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 serum 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 (e.g., 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 impact lipid traits in three non-European populations (East Asians, South Asians, and African Americans). Our results identify several novel loci associated with serum 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.

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…PCSK9 is the most established one, since it has been known for more than a decade that gain‐of‐function and loss‐of‐function variants in the PCSK9 gene increase (Abifadel et al , 2003) and decrease (Cohen et al , 2006) the risk of CAD and MI, respectively. GWAS also identified an association between common variants in the PCSK9 gene and both cholesterol levels (Teslovich et al , 2010) and CAD (Myocardial Infarction Genetics Consortium et al , 2009). PCSK9 functions in LDL cholesterol metabolism by tagging for the degradation of intracellular as well as extracellular LDL cholesterol receptors (Brautbar & Ballantyne, 2011).…”

High Triglycerides Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual Cardiovascular Risk

“…Epidemiologic studies have shown that elevated triglycerides correlate with elevated cardiovascular risk,4, 5 and the American Heart Association has long recognized that elevated triglycerides are an important marker of cardiovascular risk 6. More recently, genetic,7, 8, 9, 10, 11, 12, 13 genome‐wide analysis,14, 15, 16, 17 and mendelian randomization18, 19, 20, 21, 22 studies have suggested a causal role for triglycerides as a modifiable risk factor in the development and progression of ASCVD. Analyses from clinical data have demonstrated that lower on‐treatment triglycerides correlate with reduced cardiovascular risk 23, 24…”

Association of low‐density lipoprotein receptor‐related protein 1 rs11613352 and angiopoietin‐like 3 rs2131925 with hypertension in men—the Tampere adult population cardiovascular risk study

“…found that the polymorphism rs11613352 may contribute to attenuate cardiovascular risk by modifying plasma lipid levels in FH patients, as the TT genotype displayed a profile of lower TG and higher HDL‐C (Aledo et al., 2015). The association for lipids was similar to the GWAS study (Teslovich et al., 2010). Although a lipid association was not seen in the present male population, we confirmed it for increased HDL‐C seen with the TT genotype in 50‐year‐old women in the TAMRISK population ( p  = 0.001 for comparison of genotypes, n  = 300) (data not shown).…”

“…Men with ANGPTL3 rs2131925 (T>G) T allele had more hypertension than those with the minor genotype GG. Previously, the TT genotype has been shown to be associated with increased TG and LDL‐C (Teslovich et al., 2010). We found no statistically significant association with lipids in our male population.…”

“…For ANGPTL3 rs2131925 (T>G), men with the T allele had more hypertension than those with the minor genotype GG. Previously, the TT genotype has been shown to be associated with increased TG and LDL‐C (Teslovich et al., 2010). Association of LRP1 1 rs11613352 and ANGPTL3 rs2131925 with hypertension might imply a direct effect at the artery wall.…”