Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease.
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.


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.
Musunuru
Kiran
K
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Post
Wendy S
WS
Herzog
William
W
Shen
Haiqing
H
O'Connell
Jeffrey R
JR
McArdle
Patrick F
PF
Ryan
Kathleen A
KA
Gibson
Quince
Q
Cheng
Yu-Ching
YC
Clearfield
Elizabeth
E
Johnson
Andrew D
AD
Tofler
Geoffrey
G
Yang
Qiong
Q
O'Donnell
Christopher J
CJ
Becker
Diane M
DM
Yanek
Lisa R
LR
Becker
Lewis C
LC
Faraday
Nauder
N
Bielak
Lawrence F
LF
Peyser
Patricia A
PA
Shuldiner
Alan R
AR
Mitchell
Braxton D
BD
D000328:Adult; D001792:Blood Platelets / Q000378:metabolism*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014652:Vascular Diseases / Q000235:genetics*