Sex-specific effects of scavenger receptor class B type 1 (SR-BI) gene variants on serum lipid levels and hepatic gene expression.
ABSTRACT: BACKGROUND: Several studies have noted that genetic variants of SCARB1, a lipoprotein receptor involved in reverse cholesterol transport, are associated with serum lipid levels in a sex-dependent fashion. However, the mechanism underlying this gene by sex interaction has not been explored. METHODS: We utilized both epidemiological and molecular methods to study how estrogen and gene variants interact to influence SCARB1 expression and lipid levels. Interaction between 35 SCARB1 haplotype-tagged polymorphisms and endogenous estradiol levels was assessed in 498 postmenopausal Caucasian women from the population-based Rancho Bernardo Study. We further examined associated variants with overall and SCARB1 splice variant (SR-BI and SR-BII) expression in 91 human liver tissues using quantitative real-time PCR. RESULTS: Several variants on a haplotype block spanning intron 11 to intron 12 of SCARB1 showed significant gene by estradiol interaction affecting serum lipid levels, the strongest for rs838895 with HDL-cholesterol (p=9.2 x 10-4) and triglycerides (p=1.3 x 10-3) and the triglyceride:HDL cholesterol ratio (p=2.7 x 10-4). These same variants were associated with expression of the SR-BI isoform in a sex-specific fashion, with the strongest association found among liver tissue from 52 young women
Chiba Falek, O; Nichols, M; Suchindran, S; Guyton, JR; Ginsburg, GS; Barrett Connor, E; McCarthy, JJ
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