rs734312

This prospective study of 5,110 French individuals from the DESIR cohort investigated WFS1 gene variants (rs10010131, rs1801213, rs734312) and their associations with type 2 diabetes risk over 9 years of follow-up. The major alleles of all three variants were significantly associated with increased diabetes risk (HR 1.34-1.44, p=0.007-0.03), with the GGA haplotype showing increased risk compared to the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p=0.02). Associations were replicated in cross-sectional studies of 4,472 diabetic patients and confirmed a role for WFS1 variants in modulating insulin secretion and diabetes susceptibility.

This association study of 1,578 German non-diabetic individuals at increased type 2 diabetes risk found that the WFS1 rs10010131 variant was associated with reduced oral glucose tolerance test (OGTT)-derived insulin secretion (p=0.03). Importantly, glucose stimulation via intravenous injection did not reduce insulin secretion in carriers, indicating the variant specifically impairs glucagon-like peptide-1 (GLP-1)-induced insulin secretion (first phase p=0.007, second phase p=0.04). The genetic effect was independent of insulin sensitivity and the TCF7L2 locus.

This replication study examined four WFS1 gene SNPs (rs10010131, rs6446482, rs752854, rs734312) in a Swedish type 2 diabetes case-control study (N=1,296 cases/1,412 controls) and conducted meta-analysis of 11 studies (up to 14,139 cases and 16,109 controls). In the Swedish study, rs752854 was associated with reduced diabetes risk (OR=0.85, 95% CI=0.75-0.96, p=0.010). Meta-analysis confirmed robust association for rs10010131 and proxy variants (OR=0.89, 95% CI=0.86-0.92, p=4.9×10⁻¹¹ across all 11 studies).

This study tested WFS1 gene polymorphisms (rs10010131, rs752854, rs734312) for association with type 2 diabetes incidence in the Diabetes Prevention Program (DPP) with 3,548 participants. While no statistically significant associations were found in the overall cohort, white participants homozygous for protective alleles showed a trend toward reduced diabetes risk in the lifestyle intervention arm (HR 0.30 for rs752854, p=0.048). Genome-wide association data identified rs10012946 in strong LD with these variants, which was significantly associated with type 2 diabetes (allelic OR 0.85, 95% CI 0.75-0.97, p=0.026).

This study examined WFS1 genetic variants (rs734312 His611Arg and rs10010131) in relation to type 2 diabetes risk phenotypes across 9,772 Danish individuals. The diabetes-associated A allele of rs734312 showed borderline significant association with type 2 diabetes (OR=0.93, p=0.024) and demonstrated glucose-tolerance-dependent effects on insulin secretion: in individuals with abnormal glucose regulation, the risk allele was associated with decreased insulinogenic index (p=0.025) and reduced 30-min post-oral glucose load insulin (p=0.047), while in glucose-tolerant individuals it was associated with increased fasting insulin (p=0.019) and insulin resistance (HOMA-IR p=0.026).