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Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene–gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein–protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between  HMGCR  and a locus near  LIPC  in their effect on HDL-C levels (Bonferroni corrected  P   c  = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene–gene interaction in the European American cohorts from the Framingham Heart Study ( P   c  = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA;  P   c  = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC ( P   c  = 0.004) and in the Hispanic American sample from MESA ( P   c  = 0.04). Both  HMGCR  and  LIPC  are involved in the metabolism of lipids, and genome-wide association studies have previously identified  LIPC  as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene–gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations.

Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in Multi-Ethnic Populations