Association of Single Nucleotide Polymorphisms on Chromosome 9p21.3 With Platelet Reactivity A Potential Mechanism for Increased Vascular Disease

被引：43

作者：

Musunuru, Kiran ^{[2
]}

Post, Wendy S. ^{[2
]}

Herzog, William ^{[2
]}

Shen, Haiqing ^{[1
]}

O'Connell, Jeffrey R. ^{[1
]}

McArdle, Patrick F. ^{[1
]}

Ryan, Kathleen A. ^{[1
]}

Gibson, Quince ^{[1
]}

Cheng, Yu-Ching ^{[1
]}

Clearfield, Elizabeth ^{[1
]}

Johnson, Andrew D. ^{[7
,8
]}

Tofler, Geoffrey ^{[9
]}

Yang, Qiong ^{[7
,10
]}

O'Donnell, Christopher J. ^{[7
,8
]}

Becker, Diane M. ^{[3
]}

Yanek, Lisa R. ^{[3
]}

Becker, Lewis C. ^{[2
]}

Faraday, Nauder ^{[4
]}

Bielak, Lawrence F. ^{[5
]}

Peyser, Patricia A. ^{[5
]}

Shuldiner, Alan R. ^{[1
,6
]}

Mitchell, Braxton D. ^{[1
]}

机构：

[1] Univ Maryland, Div Endocrinol Diabet & Nutr, Sch Med, Baltimore, MD 21201 USA

[2] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Dept Med, Div Gen Internal Med, Baltimore, MD USA

[4] Johns Hopkins Univ, Dept Med, Dept Anesthesiol Crit Care Med, Baltimore, MD USA

[5] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[6] Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21218 USA

[7] NHLBI, Framingham Heart Study, Framingham, MA USA

[8] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA

[9] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia

[10] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

来源：

CIRCULATION-CARDIOVASCULAR GENETICS | 2010年 / 3卷 / 05期

基金：

美国国家卫生研究院;

关键词：

genetics; cardiovascular diseases; coronary disease; stroke; blood platelets; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; HEART-DISEASE; 4; SNPS; MYOCARDIAL-INFARCTION; CONFER RISK; LOCUS; SUSCEPTIBILITY; REPLICATION; VARIANTS;

D O I：

10.1161/CIRCGENETICS.109.923508

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 approximate to 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. (Circ Cardiovasc Genet. 2010;3:445-453.)

引用

页码：445 / 453

页数：9

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