Significant associations between rs10757274, rs2383206, rs10757278 and rs1333049 polymorphisms and diabetes and coronary artery disease were observed in patients with well-known multi-vessel CAD. Furthermore, our results suggested a significant difference in overall mortality and death from cardiac causes according to the rs2383206 in this patient sample that already presents well established risk factors and multivessel coronary artery disease.
Currently, genome-wide association identified a single region on chromosome 9p21.3 associated with CHD and MI risks [3
] independently of traditional risk factors including age, gender, obesity, smoking, hypertension and hyperlipidemia [8
]. Besides, Musunuru et al. have proposed that risk alleles at 9p21.3 locus may have pleiotropic effects on MI, CAD and stroke risks, possibly through their influence on platelet reactivity [23
]. Helgadottir et al. [4
] identified the rs10757278 that showed significant association with MI risk and that approximately 21% of individuals in the population are homozygous for this variant with estimated risk of suffering MI equal 1.64 times as great as that of non-carriers. McPherson et al. [3
] identified 2 SNPs in the same genomic region, rs10757274 and rs2383206, both associated with risk, in 6 independent studies comprising more than 23,000 individuals and with a population-attributable fraction of 10% to 15%. Moreover, the Wellcome Trust Case Control Consortium [24
] identified rs1333049 in this region, also showing strong association with CHD risk and a study that combined the Wellcome Trust Case Control Consortium data with data from Germany also confirmed the chromosome 9 region and identified 6 additional novel candidate genes for CHD [12
In our study, we observed the association of the SNP rs2383206 to CAD within a group of patients with multi-vessel coronary disease that can reveal higher incidence of death depending on its genotype. The reports cited here have provided evidences of increased risk or susceptibility to develop CAD in case–control studies and our findings have showed significant differences of cardiovascular events within a sick population.
Regarding baseline clinical characteristics, our results showed association of all studied SNPs with prevalence of type 2 diabetes mellitus in these patients. In fact, the GG genotypes for the rs10757274, rs2383206 and rs10757278 suggested protection while the GG genotype for the rs1333049 indicated risk. Recent reports have discussed the association of these loci on chr9p21 with type 2 diabetes mellitus suggesting the sharing of pathogenic mechanisms with heart disease [14
]. Studying the association between the SNP rs2383206 and CAD, Doria et al. observed increased CAD risk in the presence of poor glycemic control in type 2 diabetes [25
]. Gori et al. [26
] have confirmed that rs2891168 and rs10811661 are independently associated with MI and type 2 diabetes, respectively in an Italian population as reported by the PROCARDIS group [27
In a recent study, Wang et al. observed a significant association of homozygous CC genotype for the rs1333049 with CAD in non-diabetic Chinese Han population but not in type 2 diabetic patients. Besides, they have demonstrated that CC or GC genotype carriers had a more severe plaque progression than GG genotype carriers [28
]. The GRACE genetics study has provided evidence that the association of rs1333049 with recurrent MI or cardiac death was independent of all other risk factors [29
]. Another recent report showed that the 9p21 variant rs10116277 is independently associated with all-cause mortality after primary CABG surgery in Whites and significantly improves the predictive value of the logistic EuroSCORE [30
]. Here, we find that not only the rs1333049 CC genotype is more associated with serious CAD but also rs10757278 GG genotype; both are related to triple-vessel disease.
Finally, with respect to the end points, there was higher incidence of overall mortality in patients with GG genotype for rs2383206, which remained significantly associated with a 1.75-fold increased risk of overall mortality (CI 95%
1.08 – 2.82) even after adjustment of a Cox multivariate model. The association of this SNP with death can be observed in the survival curves where not only overall mortality was affected but cardiac death too.
There are some limitations in our study. First, we were not able to perform replication studies in a similar sample because there are very few studies similar to MASSII in the literature. However, our main findings are in accordance to previous studies including a current study published in this journal which confirmed a strong association of the 9p21.3 locus with MI particularly in patients with a positive family history [30
]. Second, our sample size only provide 80% power to detect an association with overall mortality with an effect size of 3.4-3.9 for the polymorphisms and correction for multiple testing was not performed. We recognize that such effects are highly unlikely for common genetic variants and reaffirm the need for the development of increased samples of multivessel CAD patients with long-time follow-up period for the identification of more modest effects. In addition, we observed that diabetes and smoking did not have significant effects in the multivariate analysis for overall mortality, as well as gender and hypertension, probably because our sample is composed of more severe patients. Third, it is not possible to completely exclude the interaction between the use of concomitant drugs, other genetic markers, ethnicity and other covariates on our findings [31