Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study

Abstract

Aims/hypothesis We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. Methods We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. Results We observed statistically significant associations between the major alleles of the three variants and prevalent Diabetologia (2011) 54:554-562 DOI 10.1007/s00125-010-1989 type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p=0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p=0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA 1c levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. Conclusions/interpretation The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

“…Therefore, carriage of the susceptibility WFS1 variant is related to impaired glucoseinduced insulin response resulting from β-cell dysfunction. These results are in accordance with findings in other populations reporting the relationship between the carriage of various diseaseassociated variants of WFS1 and altered insulin secretion in response to glucose stimulation [10,[19][20][21] and lower pancreatic β-cell function [22]. SNP rs734312 is a missense mutation that is situated in the last exon (exon 8) of WFS1, and leads to an amino acid (aa) substitution of histidine to arginine in codon 611 (H611R).…”

“…First evidence for association between WFS1 and T2D was obtained in a small study involving an analysis of UK families with T2D [4]. The association between WFS1 and T2D was then repeatedly replicated by several large-scale studies in various Caucasian populations [5][6][7][8][9][10]. In WFS1, several single nucleotide polymorphisms (SNPs) showed significant associations with T2D, with SNP rs10010131 as the most strongly diseaseassociated marker (for a minor allele A, odds ratio (OR) = 0.89, 95% confidence interval (95% CI) = 0.86-0.92) [7].…”

Epidemiology and genetic determinants of progressive deterioration of glycaemia in American Indians: the Strong Heart Family Study

“…The WFS1 variant has been prospectively associated with development of type 2 diabetes among individuals of European ancestry [43]. For remaining loci, differences in linkage disequilibrium of the genotyped SNP with the ‘causal’ variant(s) between American Indians and individuals of European ancestry, the population used in the discovery, may account for some of the negative findings.…”

Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing

“…WFS1 null mice and genetic association studies suggest a role for the WFS1 gene in insulin secretion [48,49,50]. In a previous study, another novel variant, c.2017T>C:p.Arg703Cys, in WFS1 was also found in a Norwegian MODY family; however, the authors suggested further evaluation of the role of WFS1 in MODY considering an inheritance pattern [12].…”