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Journal of Lipid Research, Vol. 50, 565-573, March 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

The effects of ABCG5/G8 polymorphisms on plasma HDL cholesterol concentrations depend on smoking habit in the Boston Puerto Rican Health Study^*,

Mireia Junyent, Katherine L. Tucker, Caren E. Smith, Antonio Garcia-Rios, Josiemer Mattei, Chao-Qiang Lai, Laurence D. Parnell and Jose M. Ordovas¹

The Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University School of Medicine, Boston, MA

^* This work was supported by the National Institutes of Health, National Institute on Aging, Grant Number 5P01AG-023394-02, National Heart, Lung and Blood Institute, Grant HL-54776, and National Institute of Diabetes and Digestive and Kidney Diseases, Grant DK-075030; and contracts 53-K06-5-10 and 58-1950-0-001 from the United States Department of Agriculture Research Service. M.J. is supported by a grant from the Fulbright-Spanish Ministry of Education and Science (reference 2007-1086).

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of five tables.

Published, JLR Papers in Press, November 12, 2008.

¹ To whom correspondence should be addressed. e-mail: jose.ordovas{at}tufts.edu

Low HDL-cholesterol (HDL-C) is associated with an increased risk for atherosclerosis, and concentrations are modulated by genetic factors and environmental factors such as smoking. Our objective was to assess whether the association of common single-nucleotide polymorphisms (SNPs) at ABCG5/G8 (i18429G>A, i7892T>C, Gln604GluC>G, 5U145A>C, Tyr54CysA>G, Asp19HisG>C, i14222A>G, and Thr400LysC>A) genes with HDL-C differs according to smoking habit. ABCG5/G8 SNPs were genotyped in 845 participants (243 men and 602 women). ABCG5/G8 (i7892T>C, 5U145A>C, Tyr54CysA>G, Thr400LysC>A) SNPs were significantly associated with HDL-C concentrations (P < 0.001–0.013) by which carriers of the minor alleles at the aforementioned polymorphisms and homozygotes for the Thr400 allele displayed lower HDL-C. A significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5/G8 (Gln604GluC>G, Asp19HisG>C, i14222A>G) SNPs displayed lower concentrations of HDL-C only if they were smokers (P = 0.001–0.025). Also, for ABCG8_Thr400LysC>A SNP, smokers, but not nonsmokers, homozygous for the Thr400 allele displayed lower HDL-C (P = 0.004). Further analyses supported a significant haplotype global effect on lowering HDL-C (P = 0.002) among smokers. In conclusion, ABCG5/G8 genetic variants modulate HDL-C concentrations, leading to an HDL-C-lowering effect and thereby a potential increased risk for atherosclerosis only in smokers.

Supplementary key words interaction • atherosclerosis • reverse cholesterol transport

Abbreviations: AIM, ancestral informative marker; BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; FXR, farnesoid X receptor; HDL-C, HDL-cholesterol; LD, linkage disequilibrium; LXR, liver X receptor; RCT, reverse cholesterol transport; SNP, single-nucleotide polymorphism; TG, triglyceride

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