A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry

• Authors: Brian G. Kral, Johns Hopkins University; Rasika A. Mathias, Johns Hopkins University; Bhoom Suktitipat, Johns Hopkins University; Ingo Ruczinski, Johns Hopkins University; Dhananjay Vaidya, Johns Hopkins University; Lisa R. Yanek, Johns Hopkins University; Arshed Quyyumi, Emory University; Riyaz S. Patel, Emory University; Abarmard Zafari, Emory University; Laura Vaccarino, Emory University; Elizabeth R. Hauser, Duke University; William E. Kraus, Duke University; Lewis C. Becker, Johns Hopkins University; Diane M. Becker, Johns Hopkins University
• Journal Title: Journal of Human Genetics
• Volume: Volume 56, Number 3
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B | 2011-03-01, Pages 224-229
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/jhg.2010.171
• Subjects: Biology, Genetics; Health Sciences, Public Health; Health Sciences, Epidemiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; African American; CDKN2B; coronary artery disease; genetics; 9p21; GENOME-WIDE ASSOCIATION; HEART-DISEASE; MYOCARDIAL-INFARCTION; RISK-FACTORS; SUSCEPTIBILITY LOCUS; 4 SNPS; POPULATION; SIBLINGS; INK4/ARF; JAPANESE; Stable angina; Epidemiology; Genetic variation

Abstract

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. Apparently healthy African American siblings (n548) 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 single-nucleotide polymorphisms (SNPs) across the 9p21.3 region in a generalized estimating equation 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 (odds ratio (OR)0.19, 95 confidence interval (CI): 0.07 to 0.50, P0.0008) and was replicated in a combined analysis of two additional casecontrol studies of prevalent CADMI in African Americans (n990, P0.024, OR0.779, 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.