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

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 conclu- sive. Subfractions of HDL, such as HDL 3 -C, may be better phenotypes for linkage studies. Using HDL 3 -C levels mea- sured on 907 Framingham Heart Study subjects from 330 families around 1987, we conducted a genome-wide variance components linkage analysis with 401 microsatellite mark- ers 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 chromo- some 6. Linkage analyses with additional SNPs yielded the highest LOD score of 4.0 at 129 cM on chromosome 6. Fam- ily-based association analysis revealed that SNP rs2257104 in PLAGL1 at � 143 cM was associated with multivariable adjusted HDL 3 ( P � 0.03). Further study of the linkage re- gion and exploration of other variants in PLAGL1 are war- ranted to define the potential functional variants of HDL-C metabolism. —Yang, Q., C-Q. Lai, L. Parnell, L. A. Cupples, X. Adiconis, Y. Zhu, P. W. F. Wilson, D. E. Housman, A. M. Shearman, R. B. D'Agostino, and J. M. Ordovas. Genome- wide linkage analyses and candidate gene fine mapping for HDL 3 cholesterol: the Framingham Study. J. Lipid Res. 2005. 46: 1416-1425.