Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations.
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, age(2), 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.
North
Kari E
KE
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. kari_north@unc.edu
Franceschini
Nora
N
Avery
Christy L
CL
Baird
Lisa
L
Graff
Mariaelisa
M
Leppert
Mark
M
Chung
Jay H
JH
Zhang
Jinghui
J
Hanis
Craig
C
Boerwinkle
Eric
E
Volcik
Kelly A
KA
Grove
Megan L
ML
Mosley
Thomas H
TH
Gu
Charles
C
Heiss
Gerardo
G
Pankow
James S
JS
Couper
David J
DJ
Ballantyne
Christie M
CM
Linda Kao
W H
WH
Weder
Alan B
AB
Cooper
Richard S
RS
Ehret
Georg B
GB
O'Connor
Ashley A
AA
Chakravarti
Aravinda
A
Hunt
Steven C
SC
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure; D064447:Checkpoint Kinase 2; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D055815:Young Adult
D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases