Association studies of genetic variation in the WFS1 gene and type 2 diabetes in U.K. populations.
Mutations in the WFS1 gene cause beta-cell death, resulting in a monogenic form of diabetes known as Wolfram syndrome. The role of variation in WFS1 in type 2 diabetes susceptibility is not known. We sequenced the WFS1 gene in 29 type 2 diabetic probands and identified 12 coding variants. We used 152 parent-offspring trios to look for familial association; the R allele at residue 456 (P = 0.04) and the H allele at residue 611 (P = 0.05) as well as the R456-H611 haplotype (P = 0.032) were overtransmitted to affected offspring from heterozygous parents. In a further cohort of 327 type 2 diabetic subjects and 357 normoglycemic control subjects, the H611 allele and the R456-H611 haplotype were present in more type 2 diabetic subjects than control subjects (one-tailed P = 0.06 and P = 0.023, respectively). In a combined analysis, the H611 allele was present in 60% of all diabetes chromosomes and 55% of all control chromosomes (odds ratio [OR] 1.24 [95% CI 1.03-1.48], P = 0.02), and the R456-H611 haplotype was significantly more frequent in type 2 diabetic subjects than in control subjects (60 vs. 54%, OR 1.29 [95% CI 1.08-1.54], P = 0.0053). Our results provide the first evidence that variation in the WFS1 gene may influence susceptibility to type 2 diabetes.
Minton
Jayne A L
JA
Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health, The Medical School, University of Birmingham, Edgbaston, UK.
Hattersley
Andrew T
AT
Owen
Katharine
K
McCarthy
Mark I
MI
Walker
Mark
M
Latif
Farida
F
Barrett
Timothy
T
Frayling
Timothy M
TM
D000328:Adult; D000483:Alleles; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D006113:United Kingdom
D017931:DNA Primers; D008565:Membrane Proteins; C114987:wolframin protein; D004247:DNA