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Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study.

TitleGenetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study.
Publication TypeJournal Article
Year of Publication2006
AuthorsLee CR, North KE, Bray MS, Fornage M, Seubert JM, Newman JW, Hammock BD, Couper DJ, Heiss G, Zeldin DC
JournalHum Mol Genet
Volume15
Issue10
Pagination1640-9
Date Published2006 May 15
ISSN0964-6906
KeywordsAfrican Americans, Coronary Disease, Epoxide Hydrolases, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Haplotypes, Humans, Male, Middle Aged, Polymorphism, Genetic, Risk, Smoking
Abstract

Endothelial dysfunction contributes to the development of coronary heart disease (CHD). Soluble epoxide hydrolase metabolizes epoxyeicosatrienoic acids in the vasculature and regulates endothelial function. We sought to determine whether genetic variation in soluble epoxide hydrolase (EPHX2) was associated with the risk of CHD. We genotyped 2,065 Atherosclerosis Risk in Communities study participants (1,085 incident CHD cases, 980 non-cases) for 10 previously identified polymorphisms in EPHX2. Using a case-cohort design, associations between incident CHD risk and both non-synonymous EPHX2 polymorphisms and phase-reconstructed haplotypes were evaluated using proportional hazards regression. Individuals carrying the K55R polymorphism variant allele demonstrated higher apparent soluble epoxide hydrolase activity in vivo. Presence of the K55R variant allele was significantly more common among Caucasian CHD cases when compared with non-cases (20.8% versus 15.3%, respectively, P=0.012), and was associated with significantly higher risk of incident CHD (adjusted hazard rate ratio 1.45, 95% confidence interval 1.05-2.01, P=0.026). A significant association between the K55R variant allele and risk of CHD was not observed in African-Americans. The distribution of reconstructed haplotypes were significantly different in Caucasian cases when compared with non-cases (P=0.021). Significant differences in haplotype distribution were not observed in African-Americans (P=0.315). Genetic variation in EPHX2 was significantly associated with risk of incident CHD in Caucasians, implicating EPHX2 as a potential cardiovascular disease-susceptibility gene.

DOI10.1093/hmg/ddl085
Alternate JournalHum Mol Genet
PubMed ID16595607
PubMed Central IDPMC2040335
Grant ListES012856 / ES / NIEHS NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
NL59699-06A1 / / PHS HHS / United States
NS41466 / NS / NINDS NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
Z01 ES025034-13 / / Intramural NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
F32 ES012856 / ES / NIEHS NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
R01 ES002710 / ES / NIEHS NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
P42 ES004699 / ES / NIEHS NIH HHS / United States
HL073366 / HL / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
R01 NS041466 / NS / NINDS NIH HHS / United States
R01 HL073366 / HL / NHLBI NIH HHS / United States
ES02710 / ES / NIEHS NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
R37 ES002710 / ES / NIEHS NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01HC55020 / HL / NHLBI NIH HHS / United States
R01 HL069126 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
HL69126 / HL / NHLBI NIH HHS / United States
ES04699 / ES / NIEHS NIH HHS / United States