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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Available from: Viola Vaccarino, Oct 08, 2015
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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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    ABSTRACT: Survivorship is a trait characterized by endurance and virility in the face of hardship. It is largely considered a psychosocial attribute developed during fatal conditions, rather than a biological trait for robustness in the context of complex, age-dependent diseases like coronary artery disease (CAD). The purpose of this paper is to present the novel phenotype, survivorship in CAD as an observed survival advantage concurrent with clinically significant CAD. We present a model for characterizing survivorship in CAD and its relationships with overlapping time- and clinically-related phenotypes. We offer an optimal measurement interval for investigating survivorship in CAD. We hypothesize genetic contributions to this construct and review the literature for evidence of genetic contribution to overlapping phenotypes in support of our hypothesis. We also present preliminary evidence of genetic effects on survival in people with clinically significant CAD from a primary case-control study of symptomatic coronary disease. Identifying gene variants that confer improved survival in the context of clinically appreciable CAD may improve our understanding of cardioprotective mechanisms acting at the gene level and potentially impact patients clinically in the future. Further, characterizing other survival-variant genetic effects may improve signal-to-noise ratio in detecting gene associations for CAD.
    Frontiers in Genetics 09/2013; 4:191. DOI:10.3389/fgene.2013.00191
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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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    ABSTRACT: Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations.
    BMC Medical Genetics 07/2013; 14(1):75. DOI:10.1186/1471-2350-14-75 · 2.08 Impact Factor
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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. "
    Human Genetic Diseases, Edited by Plaseska-Karanfilska D, 09/2011: pages 129-160; InTech Open Access Publisher., ISBN: 978-953-307-936-3
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