A Common Variant in the CDKN2B Gene on Chromosome 9p21 Protects Against Coronary Artery Disease in Americans of African Ancestry

Department of Medicine, The Johns Hopkins GeneSTAR Research Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Journal of Human Genetics (Impact Factor: 2.46). 01/2011; 56(3):224-9. DOI: 10.1038/jhg.2010.171
Source: PubMed


A 58kb region on chromosome 9p21.3 has consistently shown strong association with coronary artery disease (CAD) in multiple genome-wide association studies in populations of European and East Asian ancestry. In this study we sought to further characterize the role of genetic variants in 9p21.3 in African American individuals.

Methods and Results
Apparently healthy African American siblings (n=548) of patients with documented CAD <60 years of age were genotyped and followed for incident CAD for up to 17 years. Tests of association for 86 SNPs across the 9p21.3 region in a GEE logistic framework under an additive model adjusting for traditional risk factors, family, follow-up time, and population stratification were performed. A single SNP within the CDKN2B gene met stringent criteria for statistical significance, including permutation-based evaluations. This variant, rs3217989, was common (minor allele [G] frequency 0.242), conveyed protection against CAD (OR=0.19, 95% CI: 0.07 to 0.50, p=0.0008) and was replicated in a combined analysis of two additional case/control studies of prevalent CAD/MI in African Americans (n=990, p=0.024, OR= 0.779, 95% CI: 0.626-0.968).

This is the first report of a CAD association signal in a population of African ancestry with a common variant within the CDKN2B gene, independent from previous findings in European and East Asian ancestry populations. The findings demonstrate a significant protective effect against incident CAD in African American siblings of persons with premature CAD, with replication in a combination of two additional African American cohorts.

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    • "Briefly, A single nucleotide polymorphism (rs3217989) corresponding to cyclin-dependent kinase inhibitor-2B (CDKN2B) in the 9p21 region was protective against incident CAD in a sample of 548 African Americans [OR = 0.19, 95% CI = 0.07–0.50, p = 0.0008, a finding that was further replicated in a larger combined sample of 990 African Americans (Kral et al., 2011)]. The ADA * 2 allele in the adenosine deaminase (ADA) gene was hypothesized by Safranow et al. (2007) to modulate cardioprotection via its indirect effects on levels of adenosine—a potent cardioprotective agent. "
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    • "Overall, ten of these 24 nominally associated SNPs localized within this smaller AA region, but fourteen lay outside this AA region but still within the larger EA region (Additional file 1: Table S5). However, neither the strongest 9p21 EA SNPs for CAC (rs1333049) or CAD (rs4977574) in EA nor rs6475606 or rs3217989 at 9p21, recently reported to be associated with CHD in AA [40] were among these nominally significant signals (Figure 3 and Additional file 1: Table S5). "
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    • "As more geographic populations are studied with high density genotype arrays it is also becoming apparent that allele frequencies for the relevant disease markers can vary widely. For instance, what is true for Europeans may not be for Africans, such is example the Type 2 Diabetes protective allele with increased frequency in non-Africans compared to Africans (Silander et al., 2009; Kral et al., 2011). These emerging data must be incorporated into a strategy that positions genomic medicine for a clinical role. "

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