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Papers In Press, published online ahead of print October 1, 2005
J. Lipid Res., doi:10.1194/jlr.M500137-JLR200

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Journal of Lipid Research, Vol. 46, 2202-2213, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia

Yi Yu^*, Diego F. Wyszynski^*, Dawn M. Waterworth, Steven D. Wilton, Philip J. Barter^**, Y. Antero Kesäniemi, Robert W. Mahley, Ruth McPherson^***, Gérard Waeber, Thomas P. Bersot, Qianli Ma^*, Sanjay S. Sharma, Douglas S. Montgomery, Lefkos T. Middleton, Scott S. Sundseth, Vincent Mooser, Scott M. Grundy and Lindsay A. Farrer^1,*

^* Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA
Medical Genetics, Genetic Research, GlaxoSmithKline, Collegeville, PA
Australian Neuromuscular Research Institute, Perth, Western Australia, Australia
^** Heart Research Institute, Sydney, Australia
Department of Internal Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, and American Hospital, Istanbul, Turkey
^*** University of Ottawa Heart Institute, Ottawa, Canada
Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX

The online version of this article (available at http://www.jlr.org) contains an additional four figures.

Published, JLR Papers in Press, August 1, 2005. DOI 10.1194/jlr.M500137-JLR200

¹ To whom correspondence should be addressed. e-mail: farrer{at}bu.edu

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD) = 3.34] and at 17q12 (LOD = 3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD = 3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD = 3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD = 3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD = 3.05) and on chromosome 5 in the entire group of families (LOD = 2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD = 4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD = 3.72).

These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.

Abbreviations: cM, centimorgan; CVD, cardiovascular disease; FCHL, familial combined hyperlipidemia; GEMS, Genetic Epidemiology of Metabolic Syndrome; HDL-C, high density lipoprotein-cholesterol; LDL-C, low density lipoprotein-cholesterol; LOD, logarithm of the odds ratio; QTL, quantitative trait locus; TC, total cholesterol; TG, triglyceride

Supplementary key words cardiovascular disease • epistatic effects • genetic linkage analysis • metabolic syndrome • variance components analysis

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