Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease

Abstract

Objective: The aim of this study is to discover common variants in 6 lipid metabolic genes and construct and validate a genetic risk score (GRS) based on the joint effects of genetic variants in multiple genes from lipid and other pathobiologic pathways.

Background: Explaining the genetic basis of coronary artery disease (CAD) is incomplete. Discovery and aggregation of genetic variants from multiple pathways may advance this objective.

Methods: Premature CAD cases (n = 1,947) and CAD-free controls (n = 1,036) were selected from our angiographic registry. In a discovery phase, single nucleotide polymorphisms (SNPs) at 56 loci from internal discovery and external reports were tested for associations with biomarkers and CAD: 28 promising SNPs were then tested jointly for CAD associations, and a GRS consisting of SNPs contributing independently was constructed and validated in a replication set of familial cases and population-based controls (n = 1,320).

Results: Five variants contributed jointly to CAD prediction in a multigenic GRS model: odds ratio 1.24 (95% CI 1.16-1.33) per risk allele, P = 8.2 x 10(-11), adjusted OR 2.03 (1.53-2.70), fourth versus first quartile. 5-SNP genetic risk score had minor impact on area under the receiver operating characteristic curve (P > .05) but resulted in substantial net reclassification improvement: 0.16 overall, 0.28 in intermediate-risk patients (both P < .0001). GRS(5) predicted familial CAD with similar magnitude in the validation set.

Conclusions: The Intermountain Healthcare's Coronary Genetics study demonstrates the ability of a multigenic, multipathway GRS to improve discrimination of angiographic CAD. Genetic risk scores promise to increase understanding of the genetic basis of CAD and improve identification of individuals at increased CAD risk.

Figure 1. Prevalence of Angiographic CAD by Count GRS₅ Score

Percent CAD across GRS₅ categories was highly significant (p-trend=8.2×10⁻¹¹). Reference mean count GRS score is 6.3.