Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations

Authors

Kari E. North, UNC Gillings School of Global Public Health
Nora Franceschini, UNC Gillings School of Global Public Health
Christy L. Avery, UNC Gillings School of Global Public Health
Lisa Baird, University of Utah School of Medicine
Mariaelisa Graff, UNC Gillings School of Global Public Health
Mark Leppert, University of Utah School of Medicine
Jay H. Chung, National Heart, Lung, and Blood Institute (NHLBI)
Jinghui Zhang, Center for Biomedical Informatics & Information Technology
Craig Hanis, University of Texas Health Science Center at Houston
Eric Boerwinkle, University of Texas Health Science Center at Houston
Kelly A. Volcik, University of Texas Health Science Center at Houston
Megan L. Grove, University of Texas Health Science Center at Houston
Thomas H. Mosley, University of Mississippi School of Medicine
Charles Gu, Washington University School of Medicine in St. Louis
Gerardo Heiss, UNC Gillings School of Global Public Health
James S. Pankow, University of Minnesota Twin Cities
David J. Couper, UNC Gillings School of Global Public Health
Christie M. Ballantyne, Baylor College of Medicine
W. H. Linda Kao, Johns Hopkins University
Alan B. Weder, University of Michigan Medical School
Richard S. Cooper, Stritch School of Medicine
Georg B. Ehret, Johns Hopkins University School of Medicine
Ashley A. O'Connor, Johns Hopkins University School of Medicine
Aravinda Chakravarti, Johns Hopkins University School of Medicine
Steven C. Hunt, University of Utah School of Medicine

Document Type

Article

Publication Date

12-1-2010

Abstract

Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age2, sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis. © 2009 Springer-Verlag.

Publication Source (Journal or Book title)

Acta Diabetologica

Recommended Citation

North, K., Franceschini, N., Avery, C., Baird, L., Graff, M., Leppert, M., Chung, J., Zhang, J., Hanis, C., Boerwinkle, E., Volcik, K., Grove, M., Mosley, T., Gu, C., Heiss, G., Pankow, J., Couper, D., Ballantyne, C., Linda Kao, W., Weder, A., Cooper, R., Ehret, G., O'Connor, A., Chakravarti, A., & Hunt, S. (2010). Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations. Acta Diabetologica, 47 (SUPPL. 1) https://doi.org/10.1007/s00592-009-0162-z