rs2237895

This comprehensive review synthesizes literature on gestational diabetes mellitus (GDM), demonstrating its complex multifactorial etiology involving genetic factors (SNPs in GCKR, KCNQ1, MTNR1B, TCF7L2), epigenetic modifications (DNA methylation and microRNA expression), and alterations in microbial composition across multiple body sites. While certain SNP variants are associated with GDM phenotypes globally, genetic predisposition alone does not explain disease development; lifestyle factors can modify epigenetic signatures and microbiota composition to modulate risk. Evidence indicates genes, epigenetic alterations, and microbiota can transfer from mother to offspring with long-term health consequences.

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).

A case-control study of 674 GDM patients and 690 controls combined with a meta-analysis found that the G allele of rs10830963 and T allele of rs1387153 in MTNR1B are significantly associated with increased risk of gestational diabetes mellitus (GDM). Meta-analysis of 6 studies showed rs10830963 G allele increased GDM risk in co-dominant model (OR 1.62, 95% CI 1.34-1.94) and rs1387153 T allele increased risk in co-dominant model (OR 1.53, 95% CI 1.26-1.86).

This systematic study screened 18 T2D-associated SNPs and 5 environmental factors (trans-β-carotene, cis-β-carotene, γ-tocopherol, heptachlor epoxide, PCB170) for gene-environment interactions using NHANES data (1999-2000, 2001-2002). The strongest interaction was between rs13266634 (SLC30A8) and trans-β-carotene: in subjects with low trans-β-carotene levels, the per-risk-allele OR was 1.8 (95% CI 1.3-2.6), 40% higher than the marginal effect, and this interaction withstood Bonferroni correction (p = 0.006, FDR 1.5%). Four interactions total achieved FDR < 20%, suggesting that nutrient levels modify genetic risk for T2D.

Of 40 SNPs previously associated with type 2 diabetes, 19 (48%) introduce or remove CpG sites. In 84 human pancreatic islet donors, all 16 analyzed CpG-SNPs showed statistically significant differential DNA methylation (p≤2.3×10⁻⁵). Several CpG-SNPs including rs391300 (SRR), rs5945326 (DUSP9), rs11708067 (ADCY5), rs5015480 (HHEX), rs13266634 (SLC30A8), rs1801214 (WFS1), rs564398 (CDKN2A), and rs2237895 (KCNQ1) were associated with differential gene expression, alternative splicing, or hormone secretion, suggesting DNA methylation-mediated mechanisms linking genetic variants to type 2 diabetes pathogenesis.

This study investigated three KCNQ1 SNPs (rs2237895, rs2237897, rs2283228) for association with diabetic nephropathy in 752 Chinese type 2 diabetic patients. rs2283228 showed significant association with macroalbuminuria (p<0.001, OR 6.00, 95% CI 2.68-13.41 under recessive model) and log albumin/creatinine ratio (p=0.004). Meta-analysis combining Chinese and Japanese populations confirmed both rs2283228 and rs2237897 were significantly associated with macroalbuminuria, supporting KCNQ1 as a susceptibility locus for diabetic nephropathy in East Asians.

This case-control association study examined KCNQ1 genetic variants (rs2237892 and rs2237895) in Chinese patients with type 2 diabetes to determine their association with obesity. In diabetic patients from Hong Kong and meta-analysis across Shanghai and Hong Kong cohorts, rs2237892 was associated with lower BMI (β = -0.0048 per C allele for log10BMI, p = 2.20×10⁻⁵) and reduced risk of overweight/obesity (OR = 0.890, p = 0.001). rs2237895 showed similar results with decreased BMI (β = -0.0042, p = 4.30×10⁻⁵). No associations were detected in controls.

This case-control study investigated 25 T2DM-associated SNPs in a multi-ethnic Hawaiian cohort (291 GDM cases, 734 controls) and found ethnicity-specific associations with gestational diabetes. Key findings in Filipinos included rs1113132 (EXT2, OR=1.52, p=0.028), rs1111875 (HHEX, OR=1.5, p=0.047), rs2237892 (KCNQ1, OR=0.49, p<0.001), rs10830963 (MTNR1B, OR=0.63, p=0.025), and rs13266634 (SLC30A8, OR=0.58, p=0.011). In Japanese women, rs4402960 (IGFBP2, OR=0.5, p=0.031) and rs2237892 (KCNQ1, OR=0.5, p=0.03) were significant. Pacific Islanders showed associations with rs10830963 (MTNR1B, OR=0.52, p=0.037) and rs13266634 (SLC30A8, OR=2.43, p=0.03). No SNPs showed consistent associations across all three ethnic groups.

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 case-control association study in mainland China (1,912 type 2 diabetes cases, 2,041 controls) examined three KCNQ1 variants previously identified by genome-wide association studies. All three variants (rs2237892, rs2237895, rs2237897) showed significant association with type 2 diabetes risk: rs2237892 (OR 1.23, p=1.1×10⁻⁴), rs2237895 (OR 1.23, p=7.8×10⁻⁵), and rs2237897 (OR 1.28, p=2.0×10⁻⁶). These variants were also associated with BMI, waist measurements, and glycemic traits, confirming previous findings in Asian and European populations.

This case-control study validates the association between KCNQ1 variants and type 2 diabetes in a Chinese population of 3,503 individuals. All four tested SNPs (rs2074196, rs2237892, rs2237895, rs2237897) were significantly associated with type 2 diabetes, with rs2237892 showing the strongest association (OR 1.532, 95% CI 1.381-1.698, p=5.0×10^-16). The variants appear to influence disease susceptibility through effects on pancreatic beta cell function, as evidenced by associations with insulin secretion measures.