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

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=9.2x10(-4)) and triglycerides (p=1.3x10(-3)) and the triglyceride:HDL cholesterol ratio (p=2.7x10(-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.

Figure 1

SCARB1 SNPs associated with lipid levels in an estradiol-dependent manner in postmenopausal women. Top panel - Intron/exon structure of SCARB1 isoforms, SR-BI and SR-BII; Middle two panels - P value for interaction between SCARB1 SNPs and endogenous estradiol levels for serum lipid levels in the Rancho Bernardo Study; Bottom panel - haplotype block representing associated interval (numbers are r² values measuring pairwise linkage disequilibrium between SNPs). SNPs are ordered based on their position in the gene and from left (3') to right (5') ends of the gene. TC = total cholesterol; LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; Trig = triglycerides; TGHDL = triglyceride:HDL-C ratio.

Figure 2

Effect of SCARB1 genotype on serum lipid levels by tertile of endogenous estradiol. Shown are mean values of HDL cholesterol and triglycerides with 95% confidence intervals for subjects with 0, 1 or 2 copies of the rs838895 (panels A and B) and rs838896 (panels C and D) minor alleles. Endogenous estradiol tertiles were: low (7-17 pmol/L); medium (18-24 pmol/L); high (25-58 pmol/L).

Figure 3

Sex differences in mRNA expression in human liver tissue. Shown are average ΔΔCt values with standard error bars for full length SR-BI isoform, SR-BII and overall SCARB1, all relative to PPIA control in 91 human liver tissue, controlling for effects of age and post-mortem interval.

Figure 4

mRNA expression in human liver tissue by SCARB1 genotype and sex. Results shown are average ΔΔCt values with standard error bars for A.) Full length SR-BI isoform; B.) SR-BII and C.) overall SCARB1, all relative to PPIA control. Rs838896+ refers to carrier of the G allele (GG and GC); Rs838896- refers to genotype CC.