title: A common variant in the CDKN2B gene on chromosome 9p21 protects against coronary artery disease in Americans of African ancestry.
abstract: A 58 kb 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 (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 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, 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.
authors.affiliation: Department of Medicine, The Johns Hopkins GeneSTAR Research Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. bkral@jhmi.edu
authors.forename: Brian G
authors.initials: BG
authors.lastname: Kral
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.forename: Bhoom
authors.initials: B
authors.lastname: Suktitipat
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Vaidya
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Yanek
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
authors.forename: Riyaz S
authors.initials: RS
authors.lastname: Patel
authors.forename: A Maziar
authors.initials: AM
authors.lastname: Zafari
authors.forename: Viola
authors.initials: V
authors.lastname: Vaccarino
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Becker
authors.forename: Diane M
authors.initials: DM
authors.lastname: Becker
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9; D003324:Coronary Artery Disease / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15