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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 × 10 -4 ) and triglycerides (p = 1.3 × 10 -3 ) and the triglyceride:HDL cholesterol ratio (p = 2.7 × 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 <45 years old (p = 0.002).    Conclusions  Estrogen and  SCARB1  genotype may act synergistically to regulate expression of  SCARB1  isoforms and impact serum levels of HDL cholesterol and triglycerides. This work highlights the importance of considering sex-dependent effects of gene variants on serum lipid levels.

bmc medical genetics

Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1 (SR-BI) expression in liver and association with lipid levels in a population-based study