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Genome-Wide Linkage Scan for the Metabolic Syndrome in the HERITAGE Family Study

Human Genomics Laboratory, Pennington Biomedical Research Center (R.J.F.L., T.R., C.B.), Baton Rouge, Louisiana 70808; School of Physical and Health Education and Department of Community Health and Epidemiology, Queen’s University (P.T.K.), Kingston, Ontario, Canada; Division of Biostatistics (D.C.R., T.R.), and Departments of Genetics and Psychiatry (D.C.R.), Washington University School of Medicine, St. Louis, Missouri 63110; School of Kinesiology University of Minnesota (A.S.L.), Minneapolis, Minnesota 55455; Department of Kinesiology, Indiana University (J.S.S.), Bloomington, Indiana 47405; and Department of Health and Kinesiology, Texas A&M University (J.H.W.), College Station, Texas 77845

Address all correspondence and requests for reprints to: Claude Bouchard, Ph.D., Pennington Biomedical Research Center, Human Genomics Laboratory, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: bouchac{at}pbrc.edu.

The metabolic syndrome involves multiple and interactive effects of genes and environmental factors. To identify chromosomal regions encoding genes possibly predisposing to the metabolic syndrome, we performed a genome-wide scan with 456 white and 217 black participants from 204 nuclear families of the HERITAGE Family Study, using regression-based, single- and multipoint linkage analyses on 509 markers. A principal component analysis was performed on 7 metabolic syndrome-related phenotypes. Two principal components, PC1 and PC2 (55% of the variance), were used as metabolic syndrome phenotypes. ANOVA was used to quantify the familial aggregation of PC1 and PC2. Family membership contributed significantly (P < 0.0023) to the variance in PC1 (r² = 0.38 in whites; r² = 0.55 in blacks) and PC2 (r² = 0.51; r² = 0.48). In whites, promising evidence for linkage (P < 0.0023) was found for PC1 (2 markers on 10p11.2) and PC2 (a marker on 19q13.4). Suggestive evidence of linkage (0.01 > P > 0.0023) appeared for PC1 (1q41 and 9p13.1) and PC2 (2p22.3). In blacks, promising linkage was found for PC2 on 1p34.1, and suggestive linkage was found on 7q31.3 and 9q21.1. The genome-wide scan revealed evidence for quantitative trait loci on chromosomal regions that have been previously linked with individual cardiovascular disease and type 2 diabetes risk factors. Some of these chromosomal regions harbor promising potential candidate genes.

The HERITAGE Family Study is supported by the NHLBI through Grants HL-45670 (to C.B.), HL-47323 (to A.S.L.), HL-47317 (to D.C.R.), HL-47327 (to J.S.S.), and HL-47321 (to J.H.W.). A.S.L. is partially supported by the Henry L. Taylor Endowed Professorship in Exercise and Health Enhancement. C.B. is partially supported by the George A. Bray Chair in Nutrition. R.J.S.L. is supported by a postdoctoral fellowship from the American Heart Association, Southeast affiliate (no. 0325355B). Blood drawing for lipids and iv glucose tolerance tests performed at the Clinical Center of the University of Minnesota were supported by NIH Grant MO1-RR-000400. The results of this paper were obtained using the program package S.A.G.E., which is supported by USPHS Resource Grant 1P41-RR-03655 from the National Center for Research Resources.

Abbreviations: AVF, Abdominal visceral fat; %BF, percent body fat; BMI, body mass index; HDL-C, high density lipoprotein cholesterol; IBD, identical by descent; LDL-C, low density lipoprotein cholesterol; MAP, mean arterial blood pressure; PC1, first principal component; PC2, second principal component; POMC, proopiomelanocortin; QTL, quantitative trait locus; TG, triglycerides.

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