Higher incidence of death in multi-vessel coronary artery disease patients associated with polymorphisms in chromosome 9p21

Abstract

BackgroundWe investigated whether 9p21 polymorphisms are associated with cardiovascular events in a group of 611 patients enrolled in the Medical, Angioplasty or Surgery Study II (MASS II), a randomized trial comparing treatments for patients with coronary artery disease (CAD) and preserved left ventricular function.MethodsThe participants of the MASS II were genotyped for 9p21 polymorphisms (rs10757274, rs2383206, rs10757278 and rs1333049). Survival curves were calculated with the Kaplan–Meier method and compared with the log-rank statistic. We assessed the relationship between baseline variables and the composite end-point of death, death from cardiac causes and myocardial infarction using a Cox proportional hazards survival model.ResultsWe observed significant differences between patients within each polymorphism genotype group for baseline characteristics. The frequency of diabetes was lower in patients carrying GG genotype for rs10757274, rs2383206 and rs10757278 (29.4%, 32.8%, 32.0%) compared to patients carrying AA or AG genotypes (49.1% and 39.2%, p = 0.01; 52.4% and 40.1%, p = 0.01; 47.8% and 37.9%, p = 0.04; respectively).Significant differences in genotype frequencies between double and triple vessel disease patients were observed for the rs10757274, rs10757278 and rs1333049. Finally, there was a higher incidence of overall mortality in patients with the GG genotype for rs2383206 compared to patients with AA and AG genotypes (19.5%, 11.9%, 11.0%, respectively; p = 0.04). Moreover, the rs2383206 was still significantly associated with a 1.75-fold increased risk of overall mortality (p = 0.02) even after adjustment of a Cox multivariate model for age, previous myocardial infarction, diabetes, smoking and type of coronary anatomy.ConclusionsOur data are in accordance to previous evidence that chromosome 9p21 genetic variation may constitute a genetic modulator in the cardiovascular system in different scenarios. In patients with established CAD, we observed an association between the rs2383206 and higher incidence of overall mortality and death from cardiac causes in patients with multi-vessel CAD.

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

“…In this study, CDKN2A/B (rs1333049) demonstrated a strong association with CAD, which has been previously replicated in several studies across populations from Caucasians to East Asians 3,[13][14][15][16][17][18] . Functional analyses of the effects of CAD-associated variation on 9p21 indicate that the CAD risk allele is associated with a lower p15 INK4b expression in vascular smooth muscle cells (VSMCs) and a higher level of VSMC proliferation.…”

Polymorphism of 9p21.3 Locus Is Associated with 5-Year Survival in High-Risk Patients with Myocardial Infarction

“…Such effect would be more pronounced in patients with advanced coronary atherosclerosis. It was already reported that 9p21 locus is associated with mortality in patients with multivessel coronary artery disease [26]. Another patomechanism that needs to be considered is sudden cardiac death due to probable arrhythmia that was shown in a prospective cohort [27].…”

Association between 9p21 genetic variants and mortality risk in a prospective cohort of patients with type 2 diabetes (ZODIAC-15)

“…Different pathophysiological pathways have been proposed, including the initiation and possibly progression of coronary atherosclerosis and development of multivessel coronary artery disease (CAD) [9-11]. One of these studies showed an effect of the 9p21 region on progression of plaques in the presence of already established CVD among non-diabetics, although this effect was different in patients with T2D [11].…”