rs12255372

A literature review of 70 studies examining single nucleotide polymorphisms (SNPs) associated with obesity in Mexican populations published 2011-2021. The authors identified SNPs with differential behavior in Mexican compared to Caucasian populations, including rs17782313 (MC4R), rs6548238 (TMEM18), rs6265 (BDNF), rs7498665 (SH2B1), and notably rs6232 (PCSK1) associated with early-onset obesity in Mexican youth. The review emphasizes ethnicity-dependent genetic effects on BMI heritability (40-70%) and highlights genes involved in cholesterol metabolism and adipokine signaling pathways.

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.

This retrospective pharmacogenomic analysis of 961 type 2 diabetes patients from four 24-week phase III trials examined whether TCF7L2 gene variants influence response to linagliptin (DPP-4 inhibitor). Linagliptin lowered HbA1c across all rs7903146 genotypes (CC: -0.82%, CT: -0.77%, TT: -0.57%), with significantly reduced response in homozygous risk carriers (TT vs CC: difference ~0.26%, p=0.0182), indicating that diabetes susceptibility genes contribute to inter-individual treatment response variability.

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.

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 examined TCF7L2 polymorphisms (rs12255372 and rs7903146) in 240 youth with type 2 diabetes and 999 controls (86 NHW cases, 154 African-American cases). Among African-American youth, each copy of the T allele at rs7903146 was associated with 1.97-fold increased odds for type 2 diabetes (p=0.0002), with stronger effects than previously reported in adults. No significant association was observed in non-Hispanic white youth (OR 1.09, p=0.70), suggesting different genetic contributions to early-onset type 2 diabetes by race/ethnicity.

This association study analyzed four T2D-related SNPs (rs5219, rs1801282, rs7903146, rs12255372) in 26 Yakut patients with type 2 diabetes via pyrosequencing. No statistically significant differences were found between Yakut T2D cases and control groups for KCNJ11, PPARG, or TCF7L2 polymorphisms. The study identified strong linkage disequilibrium between TCF7L2 rs7903146 and rs12255372 (D'=1, LOD=4.92) in Yakuts and demonstrated that the risk T-allele frequency of TCF7L2 SNPs is notably lower in Asian populations (3.8% in Yakuts, 2-3% in Japanese and Chinese) compared to European and African populations.

This prospective family-based cohort study examined TCF7L2 genetic variants in 1,094 Han Chinese subjects and found pleiotropic effects on diabetes progression. Variants in the exon 4 LD block (rs7903146, rs7079711, rs4506565, rs7895340) were associated with impaired insulin secretion and increased diabetes risk (hazard ratio = 2.61, p = 0.009), while 3' end variants (rs290481, rs290487) were associated with insulin resistance markers but not diabetes progression. TCF7L2 expression was inversely correlated with insulin resistance in human adipose tissue.

This case-control study in 869 Korean women with gestational diabetes mellitus (GDM) and 632 non-diabetic controls examined whether type 2 diabetes-associated genetic variants discovered in recent GWAS are also associated with GDM. Multiple variants showed significant associations with GDM, including rs7756992 and rs7754840 in CDKAL1 (OR 1.55, p=4.17×10⁻⁹), rs10811661 in CDKN2A-CDKN2B (OR 1.49, p=1.05×10⁻⁷), variants in HHEX, rs4402960 in IGF2BP2 (OR 1.18, p=0.03), rs13266634 in SLC30A8 (OR 1.24, p=0.005), and rs7903146 in TCF7L2 (OR 1.58, p=0.038).

Nested case-control study of 258 prostate cancer cases and 258 matched controls in the CLUE II prospective cohort examining genetic variants in inflammation and obesity-related genes. The IL10 -1082G>A variant (rs1800896, A allele) was positively associated with prostate cancer risk (AG vs GG: OR=1.69, 95% CI 1.10-2.60; AA vs GG: OR=1.81, 95% CI 1.11-2.96), while a TLR4 variant (rs4986790) showed inverse association, and no consistent associations were found for obesity-related gene variants.

This study examined TCF7L2 variants in 2,512 Framingham Heart Study participants and confirmed that rs7903146 T risk allele associates with increased fasting plasma glucose (p=0.01) and a 23.5% higher proinsulin/insulin ratio (p=1×10⁻⁷) compared to C/C homozygotes, supporting the hypothesis of impaired beta cell insulin processing. However, the authors found no association between TCF7L2 haplotype A and obesity measures (BMI p=0.98), suggesting previous positive associations were likely due to ascertainment bias.

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 examined whether TCF7L2 SNPs (rs7903146, rs12255372, rs7901695, rs11196205, rs7895340) are associated with cardiovascular disease (CVD) and mortality in the ARIC cohort of 13,369 participants. The T-allele of rs7903146 was not significantly associated with incident coronary heart disease, ischemic stroke, CVD, or all-cause mortality in the full cohort or when stratified by race. A weak association with incident CHD was observed in whites with prevalent diabetes (HR = 1.21, p = 0.04) but not in blacks, suggesting TCF7L2's increased health risk is specific to diabetes rather than general cardiovascular disease.

This case-control study examined three TCF7L2 SNPs (rs7901695, rs7903146, rs12255372) in 706 Spanish individuals (180 with type 2 diabetes) and found that the T allele of rs7903146 was significantly associated with increased type 2 diabetes risk (OR 1.29, 95% CI 1.06-1.57, p=0.01). The risk alleles were also associated with an elevated proinsulin:insulin ratio after oral glucose tolerance testing, suggesting TCF7L2 involvement in insulin synthesis and processing rather than just secretion.

This replication study tested newly identified type 2 diabetes susceptibility loci in a Norwegian population-based cohort of 1,638 type 2 diabetes patients and 1,858 controls. The authors confirmed associations for rs10811661 near CDKN2B (OR 1.20, p=0.004), rs9939609 in FTO (OR 1.14, p=0.006), and rs13266634 in SLC30A8 (OR 1.20, p=3.9×10⁻⁴). They found borderline association for rs4402960 in IGFBP2 (OR 1.10, p=0.074) but no support for SNPs near FLJ39370 and PKN2.

This population-based case-control study of 597 prostate cancer cases and 548 controls investigated the TCF7L2 rs12255372 SNP and prostate cancer risk. The T allele was not associated with overall prostate cancer risk but showed an association with progression/recurrence (HR=1.48, 95% CI=1.01-2.19) that was attenuated after adjustment for Gleason score and tumor stage. Interestingly, the T allele was associated with reduced prostate cancer-specific mortality (HR=0.42, 95% CI=0.19-0.89), and with metastasis risk when restricted to bone scan/biopsy/MRI confirmed cases (HR=1.88, 95% CI=1.06-3.42).

This case-control study examined TCF7L2 gene variants in 500 Chinese type 2 diabetic patients and 500 controls. Six novel SNPs were identified via exon sequencing, with only c.1,637C>A showing appreciable frequency (23% minor allele). Association testing of this variant and four previously-reported SNPs (rs7903146, rs12255372, rs290487, rs3814573) revealed only marginal trends for rs7903146 (OR 1.982, p=0.063) and rs290487 (OR 1.237, p=0.071), failing to replicate strong European associations with type 2 diabetes in this Chinese population.

This association study of 1,110 non-diabetic participants examined TCF7L2 gene polymorphisms (rs7903146, rs12255372, rs7901695) and found that risk allele carriers have specifically impaired GLP-1-induced insulin secretion (p<0.02 for rs7903146 and rs12255372), consistent with a defect in the GLP-1 signaling pathway in pancreatic beta cells rather than reduced GLP-1 secretion. This functional deficit provides a mechanistic explanation for the increased type 2 diabetes risk conferred by these variants.

This case-control study replicates the association between TCF7L2 gene variants and type 2 diabetes risk in a Dutch cohort of 502 patients and 920 controls. Two intronic SNPs (rs12255372 and rs7903146) showed significant association with disease, with minor alleles conferring modest increased risk (OR 1.29, p=0.003 for rs12255372; OR 1.41, p=4.4×10⁻⁵ for rs7903146). The population-attributable risk from TCF7L2 variants in this Dutch population is 10%.

This study investigated whether TCF7L2 gene variants associated with type 2 diabetes in European populations also confer risk in Japanese populations. The SNP rs7903146 showed significant association with type 2 diabetes in combined Japanese samples (n=1,997; OR=1.69, 95% CI 1.21–2.36, p=0.002), demonstrating that TCF7L2 is a common type 2 diabetes susceptibility gene across ethnic groups.

This replication study examined the association of TCF7L2 polymorphisms with type 2 diabetes in a Japanese population of 1,630 patients and 1,064 controls. All four tested SNPs (rs12255372, rs7903146, rs7901695, rs11196205) were significantly associated with type 2 diabetes, with rs12255372 showing the strongest association (OR=1.70, 95% CI=1.20-2.41, p=0.0024). The risk allele frequencies were substantially lower in the Japanese population compared to white populations, suggesting ethnic differences in genetic susceptibility to type 2 diabetes.

This study investigated TCF7L2 gene variants (rs12255372 and rs7903146) in relation to type 2 diabetes across three studies: the Finnish Diabetes Prevention Study (507 subjects with impaired glucose tolerance), a cross-sectional study of 1,766 men, and 238 nondiabetic offspring of type 2 diabetic patients. The TT genotype of rs12255372 was significantly associated with incident diabetes (HR=2.85, 95% CI 1.17-6.95, p=0.021 in DPS control group) and cross-sectionally with diabetes (OR=3.40, 95% CI 1.45-7.97, p=0.005). The risk allele was associated with decreased insulin secretion but not insulin resistance, with TCF7L2 expression tending to be lower in individuals carrying risk genotypes in adipose tissue.

This case-control study of 6,516 participants from the Tayside region examined two common TCF7L2 variants (rs12255372 and rs7903146) and their association with type 2 diabetes susceptibility and glucose control. The T allele of rs7903146 showed a dose-dependent effect with odds ratios of 1.36 (95% CI 1.2-1.5) for heterozygotes and 2.03 (95% CI 1.7-2.5) for homozygotes (p<1×10⁻¹²), and was associated with higher HbA1c levels and increased insulin requirement despite lower BMI.

This study replicated the association between two TCF7L2 SNPs (rs7903146 and rs12255372) and type 2 diabetes in 1,142 Swedish elderly men from the ULSAM cohort. The highest odds ratio was 2.15 (95% CI 1.20-3.85) for rs7903146. Notably, both SNPs were significantly associated with elevated plasma proinsulin levels when adjusted for insulin sensitivity, suggesting impaired beta cell function rather than insulin resistance as the mechanism for increased diabetes risk.

This case-control and quantitative trait study tested whether TCF7L2 variants (rs7903146 and rs12255372) associated with type 2 diabetes susceptibility also influence polycystic ovary syndrome (PCOS) risk. In 369 UK PCOS cases and 2574 controls, and 540 Finnish symptomatic cases and 1083 controls, rs7903146 showed no association with PCOS (p=0.51 and p=0.36, respectively) and no relationship with androgen levels, despite adequate power to detect effects similar to type 2 diabetes (OR 1.3-1.36). The findings demonstrate that despite PCOS and type 2 diabetes sharing pathophysiological features, they have distinct genetic architectures.

This family-based association study demonstrates that TCF7L2 variants rs7903146 and rs12255372 are significantly associated with high triacylglycerol (TG) levels in familial combined hyperlipidaemia (FCHL) families from both Mexican and Finnish populations. The T alleles showed odds ratios of 1.83 and 1.67 in Mexicans (p=0.005 and p=0.01, respectively) and 1.45 and 1.51 in Finns (p=0.01 and p=0.007), with each T allele copy increasing the probability of high TG by 7-8%. Additionally, TCF7L2 mRNA expression was significantly decreased in adipose tissue from FCHL and TG-affected individuals (p=0.0002).

This study replicates the strong association between TCF7L2 variants and type 2 diabetes in an Indian population of 955 patients and 399 controls. All three SNPs (rs7903146, rs12255372, rs4506565) showed significant association with diabetes (ORs 1.46-1.50, p<1×10^-4), with rs12255372 showing the strongest homozygous effect (OR 2.28). The risk allele at rs12255372 was also associated with higher fasting and 2-hour plasma glucose and increased insulin resistance in non-diabetic subjects.

Common variants in the TCF7L2 gene (rs7903146 IVS3C>T and rs12255372 IVS4G>T) are strongly associated with type 2 diabetes risk across multiple ethnic groups. In prospective analysis of 2,676 European men, the TCF7L2 variants showed increased diabetes risk over 15 years (p<0.0001). Case-control studies confirmed strong associations in European whites (OR 1.54, p<0.0001) and Indian Asians (OR 1.53, p=0.002), but no significant association in Afro-Caribbeans.

This review examines slowly progressive type 1 diabetes mellitus (SPIDDM), also known as latent autoimmune diabetes in adults (LADA), discussing its pathogenesis, diagnostic markers, and genetic associations. Key findings include T-cell-mediated insulitis and pseudoatrophic islets characteristic of type 1 diabetes, absence of amyloid deposition seen in type 2 diabetes, and identification of multiple genetic susceptibility loci including HLA haplotypes, PTPN22 rs2476601, INS rs689, CTLA4, TCF7L2 rs7903146, ZMIZ1 rs12571751, SH2B3 rs7310615, and PFKFB3 rs1983890. GAD autoantibodies and HLA genotypes are important risk factors for beta-cell failure progression.