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A polymorphism in a region of chromosome 9 appears to increase the likelihood of coronary artery disease (CAD) and its progression as well as the need for revascularization in patients with myocardial infarction (MI) before age 45. The finding regarding the prognostic value of 9p21.3, which has been tied to CAD in numerous other studies, was published in the July 19, 2011, issue of the Journal of the American College of Cardiology.

A research team led by Diego Ardissino, MD, of Azienda Ospedaliero-Unìversitaria di Parma (Parma, Italy), studied 1,508 patients who experienced a first MI before age 45 and were enrolled in the Italian Genetic Study of Early-Onset Myocardial Infarction at 125 coronary care units between 1988 and 2002.

Patients were genotyped for the 9p21.3 locus identified by the reference SNP (single nucleotide polymorphism) 1333040 and then followed to assess the incidence of cardiovascular events and progression of atherosclerosis.

Influence of Polymorphism Demonstrated

During a median follow-up of almost 10 years, there were 77 cardiovascular deaths, 223 recurrent MIs, and 383 revascularizations (230 via PCI, 153 by bypass surgery). Fifty-three patients had more than 1 MI, 85 underwent more than 1 PCI, and 2 patients had more than 1 CABG. The 9p21.3 polymorphism had a significant influence on the composite primary endpoint (cardiovascular death, recurrent MI, or revascularization), with homozygotes experiencing worse outcomes than heterozygotes. Among the individual endpoints, however, only the rate of revascularization was affected by presence of the polymorphism, accounting for a 19% increased relative risk in heterozygotes and 41% in homozygotes (table 1).

Table 1. Influence of the 9p21.3 Genotype on Outcomes

^a P value for both heterozygous and homozygous genotypes.

Angiography performed at the time of the index MI showed significant stenosis in 1,226 patients and insignificant stenosis or normal arteries in 282 patients. The 9p21 variant was associated with the presence of significant stenosis (P = 0.014) and the Duke Coronary Artery Disease Index, a prognostic measure.

During follow-up, 405 patients underwent at least 1 repeat angiography, a median 6.6 years after the index hospitalization. The median change in the Duke Coronary Artery Disease Index was 19. The 9p21.3 variant had a significant influence on progression of atherosclerosis (adjusted HR for heterozygotes 1.5; 95% CI 1.3-2.7; adjusted HR for homozygotes 2.2; 95% CI 1.3-2.7).

Narrow Focus a Limitation

The investigators say they focused on patients who experienced early-onset MI because this phenotype is strongly influenced by genetics (about 82% had a family history of CAD) and is therefore more fruitful in terms of genetic mapping. But the downside, they add, is that the genetic impact may be overestimated, so broader studies are needed to more accurately assess the overall influence of 9p21.3 variants.

In addition, they acknowledge, the findings apply only to the narrow set of early-MI patients who did not undergo revascularization (chosen to avoid the confounding effect of intervention), and so likely had a lower rate of cardiovascular events during follow-up.

Consistent with Previous Findings

In a telephone interview with TCTMD, Robert Roberts, MD, of the University of Ottawa Heart Institute (Ottawa, Canada), whose team first uncovered the 9p21 connection, said the current data confirm the findings of his recent gene dosage study (Danadona S, et al. J Am Coll Cardiol. 2010;56:479-486) but “have the added value of being longitudinal, following patients over time to determine if 9p21 predicted outcomes.”

In an accompanying editorial, Joseph B. Muhlestein, MD, of the University of Utah (Salt Lake City, UT), and Jeffrey L. Anderson, MD, of Intermountain Medical Center (Murray, UT), write that “these findings seem to support the concept of a large impact of 9p21.3 on CAD initiation and a more modest one on subsequent disease progression.” On the other hand, in line with previous reports, the study confirms the “absence of an independent impact of 9p21 on precipitation of MI or CV death after the extent of CV disease is taken into account.”

Dr. Roberts agreed, noting that 9p21 is also a risk factor for both abdominal aortic and intracranial aneurysm, which suggests that its impact centers on vessel walls rather than thrombosis or plaque rupture.

“What remains to be discovered is the actual risk-associated genetic allele(s) and its molecular biological basis,” Drs. Muhlestein and Anderson write. A major obstacle to such efforts, they point out, is that 9p.21 lies on a stretch of the chromosome that lacks conventional protein-coding genes, which makes uncovering the mechanism especially challenging.

But in recent research (Harismendy O, et al. Nature. 2011;470;264-268) turned up an interesting clue as to how 9p21.3 may exert its pathophysiological effect. The region was found to be rich in regulatory elements called enhancers that are linked to distant genes, and 9p21 polymorphisms impaired enhancer activity, thereby altering the response to inflammation in vascular endothelial cells.

Dr. Roberts said previous research has suggested that 9p21 mediates its effects in part through inflammation, although the details have yet to be worked out. In addition, he observed, the variant is known to turn off genes that inhibit cell proliferation, which is a key feature of atherosclerosis.

A Long Way to Widespread Clinical Application 

Much further research will be required to elicit the clinical potential of the 9p21.3 discovery, such as its application to genotyping for risk prediction and development of therapies that specifically target its mechanism, the editorialists say. 

Dr. Roberts agreed but commented that the kind of risk data developed in the study “suggests that it may well be incorporated into future patient management.”

Since there is currently no specific treatment that targets 9p21, it is premature to test for it routinely, Dr. Roberts said. Even so, testing makes sense for young patients with a family history of heart disease, he added, because if they are found to carry 2 copies of the variant, their risk of a future event is extremely high and they should be treated aggressively for any other known risk factors they may have.

The next step in 9p21 research is to pin down the mechanism of action, since that will make it much easier to develop a drug to inhibit the variant’s activity, Dr. Roberts said.

To put the importance of the 9p21 discovery into perspective, he pointed out that 30 genetic variants that increase the risk of CAD have now been identified, and 24 of them act through a mechanism independent of all known risk factors. “This says to us that there are a whole bunch of contributors to the development of CAD that we never knew existed before,” he concluded. 

2. Muhlestein JB, Anderson JL. The 9p21.3 genetic region and coronary heart disease: Where do we go from here? J Am Coll Cardiol. 2011;58:435-437.

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