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Editor's Note: Commentary based on Patel RS, Asselbergs FW, Quyyumi AA, et al. Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: a systematic review and meta-analysis. J Am Coll Cardiol 2014;63:2234-45.

Background

The 9p21 locus has been the subject of intense scientific scrutiny since four concomitant reports in 2007 robustly linked common polymorphisms in the region to coronary heart disease (CHD).¹ As is the case for many loci identified via genome-wide association studies, the risk variants are not related to traditional cardiovascular risk factors and lie in a linkage block without protein-coding genes. Subsequent work identified a noncoding ribonucleic acid (RNA) in the region (ANRIL) that induces expression of nearby cyclin-dependent kinase inhibitors (CDKN2a, CDKN2b) involved in regulation of the cell cycle.² The contemporary mechanistic model, in need of further refinement, thus suggests that risk variants at 9p21 are associated with reduced ANRIL expression → reduced CKDN2a/2b activity → increased cellular proliferation in the vessel wall → atherosclerotic phenotypes.

Since the initial reports, the 9p21 association with CHD has been validated in numerous case-control and prospective cohorts. However, the relationship between the polymorphisms and subsequent CAD events in those with prevalent disease remains unclear.

Methods

Patel et al. report results from a systematic review and meta-analysis of cohorts reporting relationship between 9p21 and either first or subsequent CHD events.³ A composite outcome of myocardial infarction, angina, or revascularization was used for first events with the additional inclusion of all-cause mortality in the subsequent event analysis.

Results

A total of 31 cohorts comprising 193,372 met authors' predefined selection criteria with the composite outcome noted in 15,664 of 168,209 participants in first-event analysis and 4,436 of 25,163 individuals assessed for subsequent events. As expected, a robust association was noted for first event with pooled hazard ratio per risk allele of 1.19 (95%CI 1.17 - 1.22). However, null association was noted for risk of subsequent events, HR 1.01 (95%CI 0.97 – 1.06) despite reasonable statistical power. Funnel plot analysis demonstrated no evidence of significant publication bias. Results were fairly uniform in first event analysis with increased heterogeneity noted in subsequent event cohorts.

Conclusions

Common polymorphisms at the 9p21 locus are strongly linked to first identification of CHD but not subsequent events.

Commentary/Perspective

This report is a valuable and well-conducted assimilation of available cohort data linking 9p21 variants to coronary disease. Relative limitations include the lack of access to individual level-patient data from representative cohorts, restriction of the primary analysis to those of European ancestry, and somewhat heterogenous endpoint definition and adjudication strategies.

Potential explanations for the discordant results between first and subsequent events include "index event bias," which commonly underlies positive associations with initial events but null/protective relationship with recurrence.⁴ Applying this concept to the current study, individuals who initially manifest CHD despite absence of 9p21 risk variants may disproportionately have high-risk features that overcome the 9p21-mediated effects. These other risk factors can then drive subsequent events in a fashion not easily corrected for by standard regression models. However, the authors correctly note that to date, studies have suggested relatively uniform risk attributes across genotype classes. Secondly, the competing cardiovascular risk factor profile of older patients may make any association with subsequent events more difficult to detect. In potential support of this notion, 9p21 did appear to be significantly associated with subsequent events in participants <60 years of age (HR 1.12; 95% CI 1.04 – 1.21) but not ≥60 years with nominal evidence for significant interaction (P = 0.001). Third, individuals with the 9p21 risk genotype may receive more intensive or demonstrate an enhanced response to secondary prevention measures, although we are unaware of evidence for this to date.

Potentially most importantly, the 9p21 appears to relate more to atherosclerotic phenotypes, presumably via increased smooth muscle proliferation, than plaque rupture events. Indeed, amongst participants with angiographically-confirmed coronary disease, 9p21 showed no evidence of association with acute myocardial infarction (HR 1.00; 95%CI 0.94 – 1.06) in a previous analysis.⁵

Of note to the prevention community, the null associations of 9p21 variants with traditional risk factors does not preclude meaningful gene x environment interactions that might affect penetrance.⁶ For example, a significant interaction between the 9p21 locus and diet was noted such that the risk of coronary disease amongst participants with high-risk variants was particularly pronounced in those who also consumed an unhealthy diet.⁶

Despite endorsement from multiple commercial enterprises, the incremental role of 9p21 genotyping to guide clinical decision-making remains unproven at present. However, ongoing and fundamentally important translational research on the 9p21 locus will seek additional mechanistic understanding and explore the possibility of using these insights to drive development of novel therapeutic approaches.

References

1. Roberts R. Genetics of coronary artery disease. Circ Res 2014;114:1890-903.
2. Holdt LM, Beutner F, Scholz M, et al. ANRIL expression is associated with atherosclerosis risk at chromosome 9p21. Arterioscler Thromb Vasc Biol 2010;30:620-7.
3. Patel RS, Asselbergs FW, Quyyumi AA, et al. Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: a systematic review and meta-analysis. J Am Coll Cardiol 2014;63:2234-45.
4. Dahabreh IJ, Kent DM. Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA 2011;305:822-3.
5. Reilly MP, Li M, He J, et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 2011;377:383-92.
6. Do R, Xie C, Zhang X, et al. The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study. PLoS Med 201;8:e1001106.

Keywords: Alleles, Angina Pectoris, Cardiovascular Diseases, Cell Cycle, Cell Proliferation, Coronary Artery Disease, Coronary Disease, Cyclin-Dependent Kinases, Diet, Genome-Wide Association Study, Genotype, Humans, Muscle, Smooth, Myocardial Infarction, Patient Selection, Penetrance, Prospective Studies, Publication Bias, RNA, Risk Factors, Secondary Prevention, Translational Medical Research

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