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

TitleKnowledge-driven analysis identifies a gene-gene interaction affecting high-density lipoprotein cholesterol levels in multi-ethnic populations.
Publication TypeJournal Article
Year of Publication2012
AuthorsMa L, Brautbar A, Boerwinkle E, Sing CF, Clark AG
Secondary AuthorsKeinan A
JournalPLoS Genet
Volume8
Issue5
Paginatione1002714
Date Published2012
ISSN1553-7404
KeywordsAfrican Americans, Cholesterol, HDL, Cholesterol, LDL, Epistasis, Genetic, European Continental Ancestry Group, Genome-Wide Association Study, Hispanic Americans, Humans, Hydroxymethylglutaryl CoA Reductases, Lipase, Triglycerides
Abstract

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.

DOI10.1371/journal.pgen.1002714
Alternate JournalPLoS Genet
PubMed ID22654671
PubMed Central IDPMC3359971
Grant ListR01 HL072904 / HL / NHLBI NIH HHS / United States
P50 GM065509 / GM / NIGMS NIH HHS / United States
U01 HG005715 / HG / NHGRI NIH HHS / United States
HL072904 / HL / NHLBI NIH HHS / United States
GM065509 / GM / NIGMS NIH HHS / United States
U01-HG005715 / HG / NHGRI NIH HHS / United States