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.
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.
Chiba-Falek
Ornit
O
Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
Nichols
Marshall
M
Suchindran
Sunil
S
Guyton
John
J
Ginsburg
Geoffrey S
GS
Barrett-Connor
Elizabeth
E
McCarthy
Jeanette J
JJ
D000328:Adult; D000368:Aged; D000483:Alleles; D017398:Alternative Splicing; D008076:Cholesterol, HDL / Q000097:blood; D015331:Cohort Studies; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D014280:Triglycerides / Q000097:blood
D008076:Cholesterol, HDL; D004967:Estrogens; D008055:Lipids; D020033:Protein Isoforms; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014280:Triglycerides