Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1185-1192, 24 April 2008
doi:10.1016/j.ajhg.2008.03.015
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Loci Related to Metabolic-Syndrome Pathways Including LEPR,HNF1A, IL6R, and GCKR Associate with Plasma C-Reactive Protein: The Women's Genome Health Study
Paul M. Ridker1, 2, 
, 
, Guillaume Pare1, Alex Parker3, Robert Y.L. Zee1, 2, Jacqueline S. Danik1, 2, Julie E. Buring1, David Kwiatkowski2, Nancy R. Cook1, 2, Joseph P. Miletich3 and Daniel I. Chasman1, 2
1 Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
2 Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
3 Amgen, Inc., Cambridge, MA 02139
Corresponding authorAbstract
Although elevated levels of C-reactive protein (CRP) independently predict increased risk of development of metabolic syndrome, diabetes, myocardial infarction, and stroke, comprehensive analysis of the influence of genetic variation on CRP is not available. To address this issue, we performed a genome-wide association study among 6345 apparently healthy women in which we evaluated 336,108 SNPs as potential determinants of plasma CRP concentration. Overall, seven loci that associate with plasma CRP at levels achieving genome-wide statistical significance were found (range of p values for lead SNPs within the seven loci: 1.9 × 10−8 to 6.2 × 10−28). Two of these loci (GCKR and HNF1A) are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the interleukin-6 receptor protein gene, or the CRP gene itself. The protein products of six of these seven loci are directly involved in metabolic syndrome, insulin resistance, beta cell function, weight homeostasis, and/or premature atherothrombosis. Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP's identification as a useful biomarker of risk for incident vascular disease and diabetes.
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