rs10010131

This association study examined 43 diabetes-related SNPs in relation to diastolic dysfunction and cardiovascular disease across two Swedish cohorts. HNF1B rs757210 (T-allele) was the main finding, associated with prevalent diastolic dysfunction in both the discovery cohort (MPP-RES; OR 1.21, P=0.024) and replication cohort (VARA; OR 1.38, P=0.042), and with increased risk of incident CVD (HR 1.05, P=0.042) but not CHF over 30+ years of follow-up.

Family-based study examining parent-of-origin effects (POE) on type 2 diabetes risk in 4,211 individuals from Botnia and 1,463 from the Hungarian Transdanubian Biobank. Three loci showed nominal POE, with the strongest signal at rs7578597 in THADA showing excess maternal transmission of the risk T allele to diabetic offspring (Botnia pPOE=0.01, HTB pPOE=0.045, combined pPOE=0.0006). Five CpG sites flanking rs7578597 showed differential methylation between diabetic and non-diabetic islets, supporting potential THADA imprinting. Meta-analysis confirmed association with type 2 diabetes (OR=1.24, 95% CI 1.12-1.36, p=1.96×10⁻⁵).

Association analysis of 31 GWAS-confirmed type 2 diabetes SNPs in 3,089 Indian sib pairs (2,528 for quantitative traits, 561 for diabetes) identified significant associations with intermediate traits: CDKAL1 rs7756992, TCF7L2 rs7903146 and rs12255372 with fasting glucose (β=0.009-0.01, p≤0.01); ADAM30 rs2641348, NOTCH2 rs10923931, TCF-2/HNF1B rs757210, and CDKN2A/B rs10811661 with fasting insulin and HOMA-IR (β=±0.05-0.09, p≤0.05); and THADA rs7578597 with type 2 diabetes (OR 1.5, p=0.03).

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.

Population-based study of 6,733 non-diabetic Finnish men examining associations between 19 confirmed type 2 diabetes risk loci and tissue-specific insulin resistance indices. Type 2 diabetes risk SNPs in KCNJ11 (rs5219) and HHEX (rs1111875) showed significant associations with lower liver insulin resistance (p<0.0013 and p=5.4×10⁻⁵, respectively), while the Pro12 allele of PPARG2 (rs1801282) was significantly associated with higher adipocyte insulin resistance (p=6.2×10⁻⁵).

This association study of 4,213 Danish individuals examined 25 type 2 diabetes risk variants and their association with birthweight. The study found that type 2 diabetes risk alleles near ADCY5 (rs11708067, β = -33 g, p = 0.004), CDKAL1 (rs7756992, β = -22 g, p = 0.04), and HHEX-IDE (rs1111875, β = -16 g in meta-analysis, p = 8×10⁻⁵, n = 25,164) were associated with reduced birthweight, supporting the fetal insulin hypothesis. Meta-analyses confirmed these associations and showed no strong general effect on birthweight from the 25 common type 2 diabetes risk alleles combined.

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 case-control and family-based association study tested whether 18 type 2 diabetes susceptibility loci are associated with type 1 diabetes in 7,606 type 1 diabetic cases and 8,218 controls. Only PPARG (rs1801282/Pro12Ala, OR=0.91, p=0.004) and HHEX-IDE (rs1111875, OR=0.94, p=0.003) showed evidence of association with type 1 diabetes. The authors conclude that type 1 and type 2 diabetes do not share a common genetic background, supporting the view that type 1 diabetes is primarily an autoimmune disease.

This study tests the thrifty genotype hypothesis by examining 17 confirmed type 2 diabetes susceptibility loci and 13 obesity-susceptibility loci for signatures of positive selection. Using ancestral/derived allele analysis, integrated haplotype scores (iHS), and population differentiation (FST), the authors found limited evidence supporting the thrifty genotype hypothesis. Only rs7901695 at TCF7L2 showed notably elevated FST values (0.579 between JPT+CHB and YRI populations), and FTO showed the strongest selection signal among obesity loci (iHS=1.991).

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 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).

This prospective study of 16,143 individuals from the Malmö Preventive Project (mean follow-up 23 years) investigated whether genetic variants in 26 genes previously associated with type 2 diabetes or metabolic syndrome components could predict future development of metabolic syndrome. Polymorphisms in TCF7L2 (rs7903146, OR 1.10, p=0.00097), FTO (rs9939609, OR 1.08, p=0.0065), WFS1 (rs10010131, OR 1.07, p=0.0078), and IGF2BP2 (rs4402960, OR 1.07, p=0.021) predicted metabolic syndrome development, with TCF7L2, WFS1, and IGF2BP2 acting through hyperglycemia and FTO through obesity. A composite genotype score of 17 polymorphisms predicted metabolic syndrome risk (OR 1.04, p<0.00001), with carriers of ≥19 risk alleles having 51% increased risk compared to carriers of ≤12 alleles.

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).