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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M800232-JLR200 on July 25, 2008

Papers In Press, published online ahead of print December 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800232-JLR200
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Journal of Lipid Research, Vol. 49, 2582-2589, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrationsboxs

Yingchang Lu1,*,{dagger}, Martijn E. T. Dollé{dagger}, Sandra Imholz{dagger}, Ruben van 't Slot§, W. M. Monique Verschuren{dagger}, Cisca Wijmenga§, Edith J. M. Feskens* and Jolanda M. A. Boer{dagger}

* Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
{dagger} National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
§ Complex Genetics Section, Department of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

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

Published, JLR Papers in Press, July 25, 2008.

The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sport of The Netherlands and the National Institute for Public Health and the Environment. Y. Lu is funded by grant 2006B195 of the Netherlands Heart Foundation.

1 To whom correspondence should be addressed: e-mail: kevin.lu{at}wur.nl

The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.

Supplementary key words single nucleotide polymorphism • pathway-driven approach • random coefficient model


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