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.

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Date

2010-01-19

Authors

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

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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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Journal article

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Adult, Aged, Alleles, Alternative Splicing, Cholesterol, HDL, Cohort Studies, Estrogens, Female, Genotype, Haplotypes, Humans, Lipids, Liver, Male, Middle Aged, Polymorphism, Single Nucleotide, Postmenopause, Protein Isoforms, Scavenger Receptors, Class B, Sex Factors, Triglycerides

Citation

Published Version (Please cite this version)

10.1186/1471-2350-11-9

Publication Info

Chiba-Falek, Ornit, Marshall Nichols, Sunil Suchindran, John Guyton, Geoffrey S Ginsburg, Elizabeth Barrett-Connor and Jeanette J McCarthy (2010). 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. BMC Med Genet, 11. p. 9. 10.1186/1471-2350-11-9 Retrieved from https://hdl.handle.net/10161/4353.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Chiba-Falek

Ornit Chiba-Falek

Professor in Neurology

Functional genomics
Non-coding regulatory variants in the human genome
Genetics of complex neurological diseases

Guyton

John Richard Guyton

Professor Emeritus of Medicine

Current research efforts focus on the role of niacin in clinical lipid practice. Despite the ending of a large clinical trial due to lack of benefit, niacin remains the second best lipid-modifying drug after statins. Why this trial did not replicate earlier success with niacin is a matter of great interest. Counterregulatory hormone responses may provide the answer. Another research focus is weight loss counseling in the busy clinic setting. Low glycemic dietary advice achieved average long-term weight loss of 3% (beyond 1 year) in a recently published study. One in four patients had long-term weight loss greater than 6%.

Dr. Guyton is recognized nationally as an expert in clinical management of lipid disorders and a leader in postgraduate education in this area. Both nationally and internationally, Dr. Guyton is known for his earlier work on lipid deposition in the arterial wall.

Key words: atherosclerosis, lipoproteins, statins, niacin, triglycerides, low density lipoproteins, high density lipoproteins

Ginsburg

Geoffrey Steven Ginsburg

Adjunct Professor in the Department of Medicine

Dr. Geoffrey S. Ginsburg's research interests are in the development of novel paradigms for developing and translating genomic information into medical practice and the integration of personalized medicine into health care.


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