J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400382-JLR200 on April 1, 2005

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Journal of Lipid Research, Vol. 46, 1416-1425, July 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study

Qiong Yang1,*, Chao-Qiang Lai{dagger}, Laurence Parnell{dagger}, L. Adrienne Cupples*, Xian Adiconis{dagger}, Yueping Zhu{dagger}, Peter W. F. Wilson§, David E. Housman**, Amanda M. Shearman**, Ralph B. D'Agostino{dagger}{dagger} and Jose M. Ordovas{dagger}

* Department of Biostatistics, Boston University, Boston, MA 02118
§ Department of Endocrinology, Nutrition, and Diabetes, Boston University, Boston, MA 02118
{dagger}{dagger} Department of Mathematics and Statistics, Boston University, Boston, MA 02118
{dagger} Nutrition and Genomics Laboratory, Jean Mayer-United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111
** Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139

Published, JLR Papers in Press, April 1, 2005. DOI 10.1194/jlr.M400382-JLR200

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

High density lipoprotein cholesterol (HDL-C) is inversely associated with coronary heart disease and has a genetic component; however, linkage to HDL-C is not conclusive. Subfractions of HDL, such as HDL3-C, may be better phenotypes for linkage studies. Using HDL3-C levels measured on 907 Framingham Heart Study subjects from 330 families around 1987, we conducted a genome-wide variance components linkage analysis with 401 microsatellite markers spaced ~10 centimorgan (cM) apart. Nine candidate genes were identified and annotated using a bioinformatics approach in the region of the highest linkage peak. Twenty-eight single nucleotide polymorphisms (SNPs) were selected from these candidate genes, and linkage and family-based association fine mapping were conducted using these SNPs. The highest multipoint log-of-the-odds (LOD) score from the initial linkage analysis was 3.7 at 133 cM on chromosome 6. Linkage analyses with additional SNPs yielded the highest LOD score of 4.0 at 129 cM on chromosome 6. Family-based association analysis revealed that SNP rs2257104 in PLAGL1 at ~143 cM was associated with multivariable adjusted HDL3 (P = 0.03).

Further study of the linkage region and exploration of other variants in PLAGL1 are warranted to define the potential functional variants of HDL-C metabolism.

Supplementary key words high density lipoprotein • high density lipoprotein 3 • microsatellite marker • single nucleotide polymorphism • PLAGL1


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