Large-scale pleiotropy study identifies CETP as one of six newly discovered genome-wide-significant loci for coronary artery disease (J Am Coll Cardiol 2017)

Original title: Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

J Am Coll Cardiol · 21 February 2017 · 7

Webb TR, Erdmann J, Stirrups KE, Stitziel NO, Masca NG, Jansen H, Kanoni S, Nelson CP, Ferrario PG, König IR, Eicher JD, Johnson AD et al.

This large consortium study systematically tested whether genetic variants previously identified for non-coronary artery disease (CAD) traits also associate with CAD, and undertook a comprehensive analysis of pleiotropy across all known CAD loci. In discovery analyses of 42,335 CAD cases and 78,240 controls, 29,383 common single nucleotide polymorphisms on the exome array were tested, with suggestive signals replicated in an additional 30,533 cases and 42,530 controls. Six new loci reached genome-wide significance for CAD: 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP), with risk allele frequencies ranging from 0.15 to 0.86 and odds ratios per risk allele copy ranging from 1.04 to 1.09. Of 62 total CAD loci examined, 24 (38.7%) showed association with a traditional cardiovascular risk factor and 29 (47%) showed pleiotropic associations with other diseases or traits.

Original abstract

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 × 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.