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. 2010 Jan 19:11:9.
doi: 10.1186/1471-2350-11-9.

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

Ornit Chiba-Falek  1 , Marshall Nichols, Sunil Suchindran, John Guyton, Geoffrey S Ginsburg, Elizabeth Barrett-Connor, Jeanette J McCarthy
Affiliations

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

Ornit Chiba-Falek et al. BMC Med Genet. .

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.

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Figures

Figure 1
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
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
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
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.
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References

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