Clinical InvestigationGeneticsGenetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility
Section snippets
Objectives
The primary study objectives were (1) to prospectively assess the association of four 9p21 variants in patients with early-onset, angiographically defined CAD compared with (a) matched angiographically healthy subjects and with (b) a random population sample; (2) to validate the initial findings in a separate set of cases and controls; (3) to assess the association of the 9p21 variants with 8 traditional and 2 novel (inflammatory) risk factors and with CAD distinct from myocardial infarction
Patient characteristics
Characteristics of the initial association set of cases and controls are summarized in Table I. As expected, traditional risk factors were more prevalent in cases than either control group. Lipid profile and blood pressure were more favorable in population controls, whereas they were more similar in angiographic controls compared to cases. Levels of hsCRP and LpPLA2 were higher in cases.
SNP distributions and cross correlations
Allelic frequencies and representative genotypes in the initial case and control sample sets are shown in
Summary of key results
This large study, representing a total of 3573 cases and controls, prospectively assessed and validated the value of highly correlated genetic sequence variants at 9p21.3 to predict the specific CHD phenotype of angiographic CAD in a geographically distinct, primarily Caucasian population. The study demonstrated several levels of internal consistency and was statistically robust: a precise phenotype for cases and controls was established angiographically; findings among the 4 highly linked SNPs
Conclusions
In this large, angiographically defined case-control study, variants at the 9p21 locus were found to robustly predict CAD prevalence independent of standard risk factors, extent of disease, and MI. Taken together, these results suggest a specific role for 9p21 in atherosclerosis initiation/promotion. Finally, 9p21 genotyping appears to be useful in refining risk classification in those at intermediate risk and deserves prospective clinical testing as a novel risk marker.
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Cited by (62)
The association between a variant of the cyclin-dependent kinase inhibitor 2A/B gene and risk of cardiovascular disease
2022, Gene ReportsCitation Excerpt :The GWAS studies on CVDs are still relatively limited. Among the loci, which have been proposed to be involved in the predisposition to CVDs, the 9p21 locus appears to be of importance, according to studies in the UK, Japan, South Korea, Germany and Italy (Hinohara et al., 2008; Anderson et al., 2008). Single nucleotide polymorphisms at the 9p21 locus have also been showed to be associated with sudden cardiac death (SCD), CAD and to myocardial infarction (MI) in a primary and secondary prevention setting (Bressler et al., 2010; Larson et al., 2007; Ivanova et al., 2017).
The Association of ANRIL With Coronary Artery Disease And Aortic Aneurysms, How Far Does The Gene Desert Go?
2022, Annals of Vascular SurgeryCitation Excerpt :Since the discovery of the role of the gene locus on chromosome 9p21 in CAD in 2007, many studies have sought to uncover the SNPs that are most associated with CAD,3,9,22–26 and many have attempted to determine the mechanistic role ANRIL SNPs play in the disease process.4,8,11,27,28 In one of the earliest reports, Anderson et al. in 2008 studied a large cohort of 2,121 Caucasian patients and found that 4 ANRIL SNPs rs2383206, rs2383207, rs10757278 and rs10757274 predicted CAD, when compared with age and sex matched controls (non-angiographic controls, P = 0.012-0.0008; population controls, P = 0.001-<0.0001).24 In particular, they found that rs2383206 with a minor allele frequency of 45.9% was the most predictive SNP (P < 0.0001), and was associated with angiographic CAD for heterozygote (adjusted OR=1.39, 95%CI:1.05-1.85) and homozygote (adjusted OR=1.73, 95%CI:1.26-2.37) risk alleles.
The 9p21.3 locus and cardiovascular risk in familial hypercholesterolemia
2017, Journal of Clinical LipidologyAssociation between the chromosome 9p21 locus and angiographic coronary artery disease burden: A collaborative meta-analysis
2013, Journal of the American College of CardiologyCitation Excerpt :Three large studies have demonstrated further association between 9p21 and CAD burden with a number of diseased vessels or semi-quantitative methods such as the Gensini score, suggesting that 9p21 promotes progressive atherosclerosis (12,13,24). However, other studies have not confirmed this association, and this lack of consistency has led to difficulties in reconciling association with presence but not extent of CAD (14,15). However, this meta-analysis, which includes almost all published and unpublished reports on 9p21 and angiographic CAD, convincingly demonstrates that 9p21 is associated with greater CAD burden, overall.
The study was funded by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (R01HL071878) (both in Bethesda, MD), and the Deseret Foundation, Intermountain Healthcare, Salt Lake City, UT.
This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.