Abstract
Introduction: Single nucleotide polymorphisms (SNPs) at chromosome 9p21.3 do not influence myocardial infarction, but their role in coronary artery disease (CAD) progression, burden, and outcomes is controversial. This study evaluated whether rs1333049 impacts CAD burden. Methods: Non-diabetic CAD patients enrolled in the Intermountain Heart Collaborative Study (N=1,757) were evaluated for association of rs1333049 with the Duke CAD Index (primary endpoint) and other CAD measures. Multivariable regression adjusted for potential confounders. Statistical significance of secondary endpoints was corrected for multiple comparisons. Results: No association of rs1333049 with Duke CAD Index was found for 0, 1, and 2 C alleles: 42.4 ± 16.1, 44.0 ± 17.4, 47.4 ± 17.6, respectively (p-trend=0.12, adjusted p-trend=0.11). It also did not predict the number of CAD lesions (adjusted p-trend=0.11) or the maximum CAD stenosis (adjusted p-trend=0.89). The SNP did predict the number of major vessels with proximal or left main lesions (0.56 ± 0.69, 0.62 ± 0.74, and 0.71 ± 0.77 for 0, 1, and 2 C alleles, respectively; adjusted p-trend=0.0056) and another location parameter: the number of major vessels with at least one significant stenosis (p-trend=0.0017). Rs1333049 was not associated with future events, but association with CAD presence was confirmed (p-trend<0.0001). Conclusion: Rs1333049 was not associated with CAD burden, lesion number or severity, or cardiovascular events. The SNP did strongly predict CAD presence and was associated with lesion location. These findings reaffirm that a primary role of 9p21.3 may be related to the presence of CAD rather than the clinical severity of obstructive lesions. Because follow-up angiography was not systematically performed, CAD progression could not be evaluated.
Highlights
Single nucleotide polymorphisms (SNPs) at chromosome 9p21.3 do not influence myocardial infarction, but their role in coronary artery disease (CAD) progression, burden, and outcomes is controversial
In an attempt to evaluate the issues underlying the number of diseased vessels, the present study found that the number of lesions, the clinical severity of lesions, and the burden of lesions (CAD Index) were not associated with 9p21.3
Using a large population idealized for the study of the common CAD phenotype and a preferred genotype [16], this study found no association of 9p21.3 with CAD burden, lesion number or severity, or cardiovascular events
Summary
Single nucleotide polymorphisms (SNPs) at chromosome 9p21.3 do not influence myocardial infarction, but their role in coronary artery disease (CAD) progression, burden, and outcomes is controversial. Coronary artery disease (CAD) is the leading cause of mortality in low- and high-income countries, [1] and a core set of environmental and lifestyle factors influence CAD risk [2]. A 58 kilobase region on chromosome 9p21.3 was shown in 2007 to contain common single nucleotide polymorphisms (SNPs) that are associated with CAD risk [6,7,8]. These SNPs are located at CDKN2BAS, an antisense noncoding RNA (i.e., ANRIL) [9]. That mortality risk was linked to primary cultures of smooth muscle cells having markedly increased proliferation, which may indicate decreased expression of Cdkn1a and Cdkn2b (products of the two closest genes), [10] or may indicate ANRIL regulation of some unknown gene or pathway [11]
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