rs2237892

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.

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).

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 443 T2D cases and 532 controls from a Russian population (HAPIEE cohort) investigating four polymorphisms as predictors of type 2 diabetes development over 10 years. rs7903146 in TCF7L2 was significantly associated with T2D risk (TT genotype RR 3.90, 95% CI 2.31-6.61; TC genotype RR 1.86, 95% CI 1.42-2.43; CC protective RR 0.37, 95% CI 0.29-0.49, all p<0.001). No significant associations were found for rs1799883 (FABP2), rs2237892 (KCNQ1), or rs6773957 (ADIPOQ). TCF7L2 rs7903146 retained significance in risk models for both men and women.

This comprehensive review examines the association between type 2 diabetes mellitus (T2DM) and multiple myeloma (MM) risk. Genetic variants linked to T2DM show opposite associations with MM compared to diabetes GWAS: variants like CDKN2A-2B rs2383208, IGF1 rs35767, KCNQ1 rs2237892, and MADD rs7944584 increase MM risk, while FTO rs8050136, KCNJ11 rs5215/rs5219, LTA rs1041981, and THADA rs7578597 decrease risk. The IGF1 rs35767 promoter polymorphism is strongly associated with MM risk via cell proliferation mechanisms. A meta-analysis of 20 observational studies (>3 million participants) found T2DM patients had OR=1.53 (95% CI, 1.30-1.81) for MM, and MetS patients had OR=1.39 (95% CI, 1.17-1.64), mediated through insulin resistance, hyperinsulinemia, inflammatory cytokines (IL-6, TNF-α, IL-1β), dyslipidemia, and acidosis pathways.

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

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.

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 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 genome-wide association study of type 2 diabetes in 967 Mexican cases and 343 normoglycaemic controls, meta-analyzed with a Mexican-American sample (1,804 cases, 780 controls), identified genome-wide significant associations (p<5×10⁻⁸) in HNF1A (rs7305618, OR=1.69) and CDKN2A/CDKN2B (rs1333051, OR=1.32), with suggestive associations in IGF2BP2 (rs1374910, OR=1.30), KCNQ1 (rs2237892, OR=1.26), and a novel locus near C14orf70 (rs730570, OR=1.21). Follow-up in the DIAGRAM+ European dataset confirmed HNF1A and KCNQ1 regions.

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 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.

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.