The Genotype Combination of the P2Y12 Gene Might Confer Greater Risk for Coronary Artery Disease.

BACKGROUND: The adenosine diphosphate (ADP) receptor P2Y12 plays a central role in platelet function, and this receptor is therapeutic target for thrombotic disorders. Previously, the P2Y12 gene was reported to have genetic polymorphisms, H1H2 haplotype (C139T, T744C, insertion 801A, and G52T) and C34T. The effect of these polymorphisms on the risk for arterial thrombosis, however, remains controversial. In this study, we screened the sequence variations in the P2Y12 gene, and performed case-control study to investigate the association between P2Y12 polymorphisms and coronary artery disease (CAD).

METHODS AND RESULTS: Written informed consent was obtained from all study subjects who were Japanese males. Screening of polymorphisms in the P2Y12 gene comprising exon1, exon2, and intron1 was analyzed in 20 control subjects. As a result, new haplotypes were defined: haplotype A: 145C, 139C, 744T, and 1210T, haplotype B: 145T, 139T, 744C, insertion 801A, and 1210C. The G52T and C34T polymorphism were not linked with this haplotype. We next analyzed the relationship between these P2Y12 polymorphisms and susceptibility of CAD in a case-control study. One hundred and two patients with CAD were recruited at Keio University Hospital with a diagnosis of myocardial infarction or angina pectoris. CAD patients whose coronary lesions were confirmed by coronary angiography (identified stenosis ≥50%) were eligible for this study. To match CAD patients for sex and age at diagnosis of CAD, 257 healthy control subjects were recruited at their regular checkups. They had no clinical or laboratory evidence of past vascular disorders. Genotypes of the AB, C34T, and G52T polymorphisms were determined by single nucleotide primer extension-based method. We observed that the genotype frequencies of the AB (AA vs AB+BB), C34T (CC vs CT+TT), and G52T (GG vs GT+TT) did not differ between the CAD and control groups (p= 0.0635 for AB, p=0.2090 for C34T, and p=0.0816 for G52T). When study subjects were divided into the combination of two homozygous carriers (genotype combination), the AA and 34CC genotypes, and other genotypes (others), the frequency of genotype combination in CAD patients was significantly higher than that in controls (p=0.0058). Moreover, association of the genotype combination with the prevalence of CAD, adjusted for other risk factors (body mass index, smoking, hypertension, hyperlipidemia, and diabetes mellitus), was analyzed by a multiple logistic regression model, and adjusted odds ratio was 2.0 (95% CI, 1.1–3.5, p=0.0147) for the relation between CAD and the genotype combination.

CONCLUSIONS: The combination of AA haplotype and 34CC genotype is highly associated with the risk of CAD. The present data point out the importance of genotypic combination, but not single specific polymorphism, to examine the association between CAD and P2Y12 polymorphisms.