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Author Notes:

Correspondence should be addressed to: Diane M. Becker, Sc.D., The Johns Hopkins GeneSTAR Research Program, 1830 East Monument Street, Room 8023, Baltimore, MD 21287, dbecker@jhmi.edu, Telephone: 410-955-7782, Fax: 410-955-0321

Brian G. Kral and Rasika A. Mathias contributed equally to this work.

Disclosures: None.

Subjects:

Research Funding:

This work was supported by grants HL072518 from the National Heart, Lung, and Blood Institute, and M01-RR00052 from the National Center for Research Resources, National Institutes of Health, Bethesda, MD.

Genotyping of the Emory and Duke samples at deCODE genetics was supported by NIH grant R01HL089650-02 from the National Heart, Lung and Blood Institute.

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

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

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Journal Title:

Journal of Human Genetics

Volume:

Volume 56, Number 3

Publisher:

, Pages 224-229

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2011 The Japan Society of Human Genetics. All rights reserved.

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