Influence of 9p21.3 Genetic Variants on Clinical and Angiographic Outcomes in Early-Onset Myocardial Infarction

Study Questions:

Does genetic variation at 9p21.3 affect cardiovascular (CV) outcomes following early-onset myocardial infarction (MI)?

Methods:

A total of 1,508 patients hospitalized for a first MI before the age of 45 years who underwent coronary angiography without index event coronary revascularization were genotyped for rs1333040. They were followed up for major CV events and angiographic coronary atherosclerosis progression.

Results:

In over 16,599 person-years, there were 683 cardiovascular events and 492 primary endpoints: 77 CV deaths, 223 recurrent MIs, and 383 coronary revascularizations. The rs1333040 genotype had a significant influence (p = 0.01) on the primary endpoint, with an adjusted hazard ratio of 1.19 (95% confidence interval [CI], 1.08-1.37) for heterozygous carriers and 1.41 (95% CI, 1.06-1.87) for homozygous carriers. Analysis of the individual components of the primary endpoints provided no significant evidence that the rs1333040 genotype influenced the hazard of CV (p = 0.24) or recurrent MI (p = 0.57), but did provide significant evidence that it influenced the hazard of coronary revascularization, with adjusted heterozygous and homozygous ratios of 1.38 (95% CI 1.17-1.63) and 1.90 (95% CI, 1.36-2.65) (p = 0.00015), respectively. It also significantly influenced the angiographic endpoint of coronary atherosclerosis progression (p = 0.002).

Conclusions:

In early-onset MI, the 9p21.3 variant rs1333040 affects the progression of coronary atherosclerosis and the probability of coronary artery revascularization during long-term follow-up.

Perspective:

Several genome-wide association studies have identified DNA variation at 9p21 with vascular complications. These variants reside in a noncoding region, or gene desert, so the mechanisms by which these variants affect vascular disease are still unclear, although recent studies have suggested that progression of atherosclerosis may be particularly associated with 9p21 variants. Results from this prospective study support the hypothesis that atherosclerosis is specifically affected by 9p21 variation. The young age of this population is very useful for genetic studies, although the impact of a genetic variant will likely be overestimated when compared to a more typical older population. It is somewhat surprising and interesting that ‘hard’ CV events like MI and CV death were not affected by 9p21 status in this study.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Genetic Variation, Coronary Artery Disease, Myocardial Infarction, DNA, Follow-Up Studies, Atherosclerosis, Biological Markers, Coronary Angiography, Heterozygote, Genome-Wide Association Study


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