Association of Single Nucleotide Polymorphisms on Chromosome 9p21.3 With Platelet Reactivity
Year: 2010
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations. METHODS AND RESULTS: Subjects in the initial population included 1402 asymptomatic Amish adults in whom we measured platelet reactivity (n=788) and coronary artery calcification (CAC) (n=939). Platelet reactivity on agonist stimulation was measured by impedance aggregometry, and CAC was measured by electron beam CT. Twenty-nine SNPs at the 9p21.3 locus were genotyped using the Affymetrix 500K array. Twelve correlated SNPs in the locus were significantly associated with platelet reactivity (all P≤0.001). The SNP most strongly associated with platelet reactivity, rs10965219 (P=0.0002), also was associated with CAC (P=0.002) along with 9 other SNPs (all P<0.004). Association of rs10965219 with platelet reactivity persisted after adjustment for CAC, a measure of underlying atherosclerotic burden known to affect platelet reactivity. We then tested rs10965219 for association with platelet function in 2364 subjects from the Framingham Heart Study and 1169 subjects from the Genetic Study of Aspirin Responsiveness. The rs10965219 G allele (frequency ≈51% across all 3 populations) was significantly associated with higher platelet reactivity in the Framingham Heart Study (P=0.001) and trended toward higher reactivity in the Genetic Study of Aspirin Responsiveness (P=0.087); the combined P value for metaanalysis was 0.0002. CONCLUSIONS: These results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity.
Authors: Kiran Musunuru, Wendy S. Post, William Herzog, Haiqing Shen, Jeffrey R. O'Connell, Patrick F. McArdle, Kathleen A. Ryan, Quince Gibson, Yu-Ching Cheng, Elizabeth Clearfield, Andrew D. Johnson, Geoffrey Tofler, Qiong Yang, Christopher J. O'Donnell, Diane M. Becker, Lisa R. Yanek, Lewis C. Becker, Nauder Faraday, Lawrence F. Bielak, Patricia A. Peyser, Alan R. Shuldiner, Braxton D. Mitchell
Institutions: Boston University, University of Maryland, Baltimore, The University of Sydney, Johns Hopkins University, University of Michigan, Johns Hopkins Medicine, Royal North Shore Hospital, National Heart, Lung, and Blood Institute, Framingham Heart Study, Baltimore VA Medical Center, National Heart, Lung, and Blood Institute Division of Intramural Research
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Awards: G1322502209, G1393125571, Genome-Wide Association of Platelet Phenotypes, G250621538, G3342643523, General Clinical Research Center, G36937976, Genotypic Determinants of Aspirin Response in High Risk Families, G5164707915, Genome-wide Search for CVD Gene-Environment Interactions, G628276201, Genetic Influences on Coronary Artery Calcification, The Framingham Heart Study, SNP HEALTH ASSOCIATION RESOURCE (SHARE), Mid-Atlantic Nutrition Obesity Research Center, NOVEL HEMOSTATIC CARDIAC RISK FACTORS IN FRAMINGHAM, G82803878
OpenAlex ID: W2113308396