Knowledge-driven analysis identifies a gene-gene interaction affecting high-density lipoprotein cholesterol levels in multi-ethnic populations

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 pc = 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 (pc = 0.002) and the multi-ethnic study of atherosclerosis (mesa; pc = 0.006). the interaction between these two loci is also significant in the african american sample from aric (pc = 0.004) and in the hispanic american sample from mesa (pc = 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. © 2012 ma et al.