Associations between the CDKN2A/B, ADTRP and PDGFD Polymorphisms and the Development of Coronary Atherosclerosis in Japanese Patients

Abstract

Genome-wide association studies have identified a series of susceptibility loci for coronary artery disease(CAD). The present study attempted to replicate the results for eight of these loci, CDKN2A/B(rs1333049), ADTRP(rs6903956), PDGFD(rs974819), TCF21(rs12190287), COL4A1-A2(rs4773144), HHIPL1(rs2895811), ADAMTS7(rs4380028) and UBE2Z(rs46522), in patients with pathologically defined atherosclerosis of the coronary arteries. Autopsy cases of elderly Japanese subjects were enrolled in the JG-SNP study(n=1,536). Polymorphisms were genotyped, and their associations with the coronary stenosis index(CSI) and incidence of pathological myocardial infraction(MI) were investigated. The potential combinatorial effects of the susceptibility loci were also assessed. Among the eight loci tested, three exhibited signs of positive associations. CDKN2A/B showed the most robust associations with CSI and MI(p=0.007 and OR=1.843, 95% CI 1.293-2.629, p=0.001, for CC＋CG vs. GG). In addition, ADTRP demonstrated associations with CSI and MI, although the risk allele was opposite from that observed in the original report(p=0.008 and OR=1.652, 95% CI 1.027-2.656, p=0.038 for GG vs. AA＋AG). Meanwhile, PDGFD displayed a suggestive association with CSI in women, but not men(p=0.023). CDKN2A/B and ADTRP were also found to be significantly associated with the severity of the CSI in a case-control setting. The cumulative risk allele counting of CDKN2A/B, ADTRP and PDGFD indicated an increased number of risk alleles to be associated with a higher CSI(p=4.61E-05). The present study confirmed the association between CDKN2A/B and CAD and identified a different associated risk allele of ADTRP. PDGFD was found to exhibit a gender-specific association with CAD. The combination of multiple risk alleles may be associated with a higher risk of CAD.