We assessed whether chromosome 9p21 genetic variation predicted recurrent MI, revascularization, or death in patients with established CHD (i.e., patients with history of ACS or those undergoing CABG). This study primarily focused on rs10333049, a tagSNP for the LD block containing the most commonly studied variants in this region.4
We did not find an increased risk for these outcomes in the carriers of the risk allele for rs10333049, although, the carriers of the risk allele had an earlier age at presentation and more extensive angiographic CAD compared with non-carriers in the ACS subgroup. Our findings suggest that, although polymorphisms in 9p21 could play a role in the initiation and possibly progression of coronary atherosclerosis, they have minimal role in precipitation of MI in those with established CHD at a median follow-up of ~3.2 years.
Although our findings are in contrast with the findings of an earlier study by Buysschaert et al,10
they are consistent with other studies showing that, although the presence of the risk allele for 9p21 is associated with the presence of coronary atherosclerosis, it may not be associated with the actual precipitation of MI. It is possible that the association of 9p21 with MI seen in epidemiologic cohorts is a reflection of its association with the presence of coronary atherosclerosis or its severity, as patients with coronary atherosclerosis (or more severe coronary atherosclerosis) are more likely to have MI compared with those who do not have coronary atherosclerosis. In these studies, the control group represents patients without any coronary atherosclerosis. Therefore, the association between the presence of risk allele for 9p21 and MI could be driven by the association between 9p21 and the presence of coronary atherosclerosis. If this assumption is true, then any association between 9p21 and the risk of MI would be lost once this confounding by the presence of coronary atherosclerosis is accounted for. In that respect, prior analyses have shown that although 9p21 predicts CAD diagnosis, the frequency of the risk allele for 9p21 was not higher among those patients with CAD who sustained MI versus those who did not.4
Horne et al7
also showed that the 9p21 locus was not associated with prevalent or incident MI in CAD patients, although it did predict CAD diagnosis. It is important to note in our study that all patients had established atherosclerosis (whether they were 9p21 carriers or not), and therefore, any association with subsequent risk of MI could have been accounted for by the presence of coronary atherosclerosis in both carriers and non-carriers of the risk allele on the 9p21 locus.
We did not find an association between subsequent need for revascularization in carriers of the risk allele of 9p21. Prior studies have yielded varying results with some studies showing an association between 9p21 status and CAD severity,8
whereas others have not.13-15
It is possible that the progression of atherosclerosis in those with established atherosclerosis (after the receipt of coronary stents or bypass grafts) is different compared with native coronary atherosclerosis. In that respect, our results are consistent with a recent study which did not show an association between the SNPs on the 9p21 locus with death, MI, or repeat revascularization for up to 3 years of follow-up after DES placement.9
Alternatively, these patients with established atherosclerosis were likely on good medical regimen with a higher use of evidence-based medical therapies. This might attenuate the association between the 9p21 locus and the risk of recurrent MI or recurrent revascularization in these patients.
Our findings highlight the importance of replication of initial findings in genetic studies. Although Buysschaert et al10
did find associations between 9p21 and the risk of recurrent MI at 6-month follow-up in patients with ACS, we did not find an association either in ACS patients or those undergoing CABG. This could be due to the baseline differences in populations studied and the duration of follow-up (6 months vs. ≈3.2 years). Similarly, in the study by Buysschaert et al,10
the association between recurrent MI and the presence of 9p21 was attenuated once multivariate adjustments were made (p = 0.053 for the dominant model) indicating a ≥5% probability for a type 1 error leading to positive findings. Therefore, we believe that the associations between 9p21 and the risk of recurrent events in patients with established atherosclerosis needs to be replicated in other large studies with prospective follow-up of outcomes. Alternatively, our findings could reflect a limited statistical power to show associations, although it should be noted that there were more recurrent MI events (n=231) in our ACS subgroup compared with the study from Buysschaert et al10
(n=70). Indeed, our post-hoc calculations showed that if the risk estimates obtained by Buysschaert et al were to be applied to our cohort, our study would have a >99% power to show an association (i.e., the probability of type 2 error was less than 1%). In addition, the risk estimates for some of the outcomes (, and Supplemental Tables
) were not consistent across various SNPs at the 9p21 locus and were indeed protective (albeit with small number of events) for some outcomes in carriers of the risk allele in the CABG subgroup (Supplemental Table VIII
In our study, 77% of the patients in the ACS subgroup and 79% of the patients in the CABG subgroup were carriers of at least one copy of the risk allele (C) for rs1333049. This frequency for the risk allele is higher than the reported frequency of 70.8% for the risk allele (C) in the Caucasian population in HapMap (CC 20.4%, CG 50.4%, and 29.2% GG) for rs1333049. These results are expected and likely stem from the fact that our study populations (ACS, CABG) represent patients with established atherosclerosis and therefore, these populations were enriched for the risk allele (C) for rs1333049.
We included Caucasian patients with ACS or CABG; therefore, these findings are not applicable to other racial groups/ ethnicities. It is also possible that we may not have captured all the events, although patients enrolled in TexGen receive yearly letters and annual phone calls from research nurses to completely capture all the events. In addition, the event rate for MI, revascularization in this study is comparable to some of the contemporary literature.9,16,17
Although patients with non-ST segment elevation MI (NSTEMI), ST segment elevation MI (STEMI), and unstable angina constituted the ACS cohort, these qualifying diagnoses were not separately coded in the TexGen database precluding any subgroup analyses by the type of ACS. The strengths of our analyses include a large number of events especially in the ACS subgroup to confidently evaluate outcomes, and the strict quality checks maintained by the database as described in the methods section.
SNPs on 9p21 locus were not associated with recurrent MI, need for revascularization, or mortality in patients presenting with ACS or those undergoing CABG during a 3-year follow-up period. However, individuals with the risk allele for rs1333049 presented with earlier and more extensive disease than non-carriers in the ACS subgroup. Our results indicate that although 9p21 locus may have a role in the initiation and possibly progression of coronary atherosclerosis, its role in the precipitation of MI especially in those with established atherosclerosis needs further investigation. Studies evaluating the mechanism by which 9p21 locus increases the risk of coronary atherosclerosis should focus more on factors associated with atherosclerosis initiation rather than actual precipitation of MI.