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.
Bibliographical noteFunding Information:
The following investigators are associated with the Family Blood Pressure Program: GenNet Network: Alan B. Weder (Network Director), Lillian Gleiberman (Network Coordinator), Anne E. Kwitek, Aravinda Chakravarti, Richard S. Cooper, Carolina Delgado, Howard J. Jacob, and Nicholas J. Schork. GENOA Network: Eric Boerwinkle (Network Director), Tom Mosley, Alanna Morrison, Kathy Klos, Craig Hanis, Sharon Kardia, and Stephen Turner. HyperGEN Network: Steven C. Hunt (Network Director), Janet Hood, Donna Arnett, John H. Eckfeldt, R. Curtis Ellison, Chi Gu, Gerardo Heiss, Paul Hopkins, Aldi T. Kraja, Jean-Marc Lalouel, Mark Leppert, Albert Oberman, Michael A. Province, D.C. Rao, Treva Rice, and Robert Weiss.SAPPHIRe Network: David Curb (Network Director), David Cox, Timothy Donlon, Victor Dzau, John Grove, Kamal Masaki, Richard Myers, Richard Olshen, Richard Pratt, Tom Quertermous, Neil Risch and Beatriz Rodriguez. National Heart, Lung, and Blood Institute: Dina Paltoo and Cashell E. Jaquish. Web Site: http://www.biostat.wustl.edu/fbpp/FBPP.shtml . The Family Blood Pressure Program Project is supported by cooperative agreement grants HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 from the National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the FBPP and ARIC study for their important contributions.
- Atherosclerosis Risk in Communities Study
- CHEK2 SNPs
- CHEK2 gene
- Family Blood Pressure Program
- Type 2 diabetes