Transcription factor 7 like 2 promotes metastasis in hepatocellular carcinoma via NEDD9-mediated activation of AKT/mTOR signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, and the exact mechanism of HCC is still unclear. Transcription factor 7 like 2 (TCF7L2) plays a pivotal role in cell proliferation and stemness maintenance. However, the exact mechanism of TCF7L2 in HCC remains unclear. METHODS: Clinical samples and public databases were used to analyze the expression and prognosis of TCF7L2 in HCC. The function of TCF7L2 in HCC was studied in vitro and in vivo. ChIP and luciferase assays were used to explore the molecular mechanism of TCF7L2. The relationship between TCF7L2 and NEDD9 was verified in HCC clinical samples by tissue microarrays. RESULTS: The expression of TCF7L2 was upregulated in HCC, and high expression of TCF7L2 was associated with poor prognosis of HCC patients. Overexpression of TCF7L2 promoted the metastasis of HCC in vitro and in vivo, while Knockdown of TCF7L2 showed the opposite effect. Mechanically, TCF7L2 activated neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) transcription by binding to the -1522/-1509 site of the NEDD9 promoter region, thereby increasing the phosphorylation levels of AKT and mTOR. The combination of TCF7L2 and NEDD9 could distinguish the survival of HCC patients. CONCLUSIONS: This study demonstrated that TCF7L2 promotes HCC metastasis by activating AKT/mTOR pathway in a NEDD9-dependent manner, suggesting that potential of TCF7L2 and NEDD9 as prognostic markers and therapeutic targets for HCC.

Treatment and genetic analysis of multiple supernumerary and impacted teeth in an adolescent patient.

BACKGROUND: Multiple supernumerary teeth, combined with numerous impacted teeth, can lead to various malocclusions, posing significant treatment challenges. While certain genes associated with syndromic cases of multiple supernumerary and impacted teeth have been identified, the etiologies of non-syndromic cases still largely remain elusive. CASE PRESENTATION: Here, we report a treatment of a 12-year-old boy who presented with 10 supernumerary teeth and 6 impacted teeth, accompanied by a genetic analysis to explore the underlying etiology. During the treatment, fifteen teeth were extracted, and various skilled techniques, including the closed-eruption technique and the application of by-pass arches, were utilized. Post-treatment, traction was successful for all the impacted teeth, without any tooth mobility or reduction in gingival height. Space closure, well-aligned teeth, and excellent functional occlusion were achieved. Furthermore, comprehensive genetic analysis was conducted through whole-exome sequencing on the patient and his parents, which revealed a potential link between the patient's numerous supernumerary teeth and abnormal mineralization. Notably, the p.Ser496Pro variant in the TCF7L2 gene was identified as a potential candidate variant in this patient. CONCLUSIONS: Overall, our findings not only report the treatment of a rare case involving multiple supernumerary and impacted teeth but also offer valuable insights into the molecular basis of supernumerary teeth.

Assessment of potential genetic markers for diabetic foot ulcer among Moscow residents.

PURPOSE: Diabetic foot ulcer (DFU) is one of the most severe complications of type 2 diabetes, which is manifested in chronic skin ulcers of lower extremities. DFU treatment remains complex and expensive despite the availability of well-established protocols. Early prediction of potential DFU development at the onset of type 2 diabetes can greatly improve the aftermath of this complication. METHODS: To assess potential genetic markers for DFU, a group of diabetic patients from Moscow region with and without DFU was genotyped for a number of SNPs previously reported to be associated with the DFU. RESULTS: Obtained results did not confirm previously claimed association of rs1024611, rs3918242, rs2073618, rs1800629, rs4986790, rs179998, rs1963645 and rs11549465 (respectively, in MCP1, MMP9, TNFRSF11B, TNFα, TLR4, eNOS, NOS1AP and HIF1α genes) with the DFU. Surprisingly, the t allele of rs7903146 in the TCF7l2 gene known as one of the most prominent risk factors for type 2 diabetes has shown a protective effect on DFU with OR(95%) = 0.68(0.48-0.96). CONCLUSION: Non-replication of previously published SNP associations with DFU suggests that the role of genetic factors in the DFU onset is either highly variable in different populations or is not as significant as the role of non-genetic factors.

Identification of core genes in intervertebral disc degeneration using bioinformatics and machine learning algorithms.

Background: Intervertebral Disc Degeneration (IDD) is a major cause of lower back pain and a significant global health issue. However, the specific mechanisms of IDD remain unclear. This study aims to identify key genes and pathways associated with IDD using bioinformatics and machine learning algorithms. Methods: Gene expression profiles, including those from 35 LDH patients and 43 healthy volunteers, were downloaded from the GEO database (GSE124272, GSE150408, GSE23130, GSE153761). After merging four microarray datasets, differentially expressed genes (DEGs) were selected for GO and KEGG pathway enrichment analysis. Weighted Gene Co-expression Network Analysis (WGCNA) was then applied to the merged dataset to identify relevant modules and intersect with DEGs to discover candidate genes with diagnostic value. A LASSO model was established to select appropriate genes, and ROC curves were drawn to elucidate the diagnostic value of genetic markers. A Protein-Protein Interaction (PPI) network was constructed and visualized to determine central genes, followed by external validation using qRT-PCR. Results: Differential analysis of the preprocessed dataset identified 244 genes, including 183 upregulated and 61 downregulated genes. WGCNA analysis revealed the most relevant module intersecting with DEGs, yielding 9 candidate genes. The lasso-cox method was used for regression analysis, ultimately identifying 6 genes: ASPH, CDC42EP3, FOSL2, IL1R1, NFKBIZ, TCF7L2. A Protein-Protein Interaction (PPI) network created with GENEMANIA identified IL1R1 and TCF7L2 as central genes. Conclusion: Our study shows that IL1R1 and TCF7L2 are the core genes of IDD, offering new insights into the pathogenesis and therapeutic development of IDD.

Diabetes-associated Genetic Variation in MTNR1B and Its Effect on Islet Function.

Context: Multiple common genetic variants have been associated with type 2 diabetes, but the mechanism by which they predispose to diabetes is incompletely understood. One such example is variation in MTNR1B, which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes. Objective: To characterize the effect of diabetes-associated genetic variation at rs10830963 in the MTNR1B locus on islet function in people without type 2 diabetes. Design: The association of genetic variation at rs10830963 with glucose, insulin, C-peptide, glucagon, and indices of insulin secretion and action were tested in a cohort of 294 individuals who had previously undergone an oral glucose tolerance test (OGTT). Insulin sensitivity, ß-cell responsivity to glucose, and Disposition Indices were measured using the oral minimal model. Setting: The Clinical Research and Translation Unit at Mayo Clinic, Rochester, MN. Participants: Two cohorts were utilized for this analysis: 1 cohort was recruited on the basis of prior participation in a population-based study in Olmsted County. The other cohort was recruited on the basis of TCF7L2 genotype at rs7903146 from the Mayo Biobank. Intervention: Two-hour, 7-sample OGTT. Main Outcome Measures: Fasting, nadir, and integrated glucagon concentrations. Results: One or 2 copies of the G-allele at rs10830963 were associated with increased postchallenge glucose and glucagon concentrations compared to subjects with the CC genotype. Conclusion: The effects of rs10830963 on glucose homeostasis and predisposition to type 2 diabetes are likely to be partially mediated through changes in α-cell function.

Association of TCF7L2 Gene Variant (rs12255372) with Polycystic Ovary Syndrome and its Effect Modification of the Disease Phenotype.

Polycystic ovary syndrome (PCOS) and type-2 diabetes mellitus (T2DM) share common genetic features. Transcription factor 7-like-2 (TCF7L2) is consistently studied T2DM susceptibility locus. However, limited studies on TCF7L2 have failed to demonstrate any link with the PCOS risk. Therefore, we investigated the association of TCF7L2 polymorphic variant (rs12255372) with the PCOS risk. We recruited 120 PCOS cases, diagnosed as per Rotterdam 2003 criteria, and an equal number of age-matched controls. Besides a detailed clinical assessment, subjects underwent biochemical and hormonal profiling. Genotyping for rs12255372 was done by PCR-RFLP. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95%CIs) of genotype-phenotype correlations. The PCOS cases reported fewer menstrual cycles per year and exhibited signs of hyperandrogenism. The heterozygous genotype of rs12255372 was strongly associated with the PCOS risk (OR = 2.00; 95%CI: 1.07-3.76). Unlike controls, only 3 cases harbored TT genotype, and the PCOS risk persisted in the dominant model (GT + TT) as well. Moreover, we found a synergistic effect modification by the variant genotype in the subjects who had family histories of T2DM, hirsutism, or menstrual irregularities. We report a significant association of the TCF7L2 polymorphic variant rs12255372 with the PCOS risk.

Correlation between TCF7L2 gene expression and certain biochemical parameters in type 2 diabetes mellitus.

Objectives: The transcription factor 7-like 2 gene (TCF7L2) is associated with a predisposition to type 2 diabetes mellitus (T2DM) in different ethnic populations. This article investigated the relationship between TCF7L2 gene expression and several biochemical indexes among different age categories of T2DM in a sample of the Iraqi population. Methods: One hundred and fifty blood samples were collected from three groups: young T2DM (10-35 years), old T2DM (40-80 years), and healthy control (10-65 years) groups. Both sexes were enrolled. qPCR was performed to explore the expression of the TCF7L2 gene. Biochemical tests were performed to assess hemoglobin A1C (HbA1c), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. The body mass index (BMI) was calculated. The results were statistically analyzed. Results: Patients with T2DM had higher BMI, TG, and LDL, and lower HDL than the control group. There was a strong positive correlation between hemoglobin A1C (HbA1c) and BMI, TG, and LDL and a negative correlation between HbA1c and HDL. Expression of the TCF7L2 gene showed a significant difference between old and young patients by 1.68 and 0.207 fold, respectively. These results showed that old patients had higher gene expression than young patients. Conclusion: TCF7L2 gene expression was affected by age, with higher expression in old T2DM patients. This may influence beta cell functions and insulin secretion.

IL-33/soluble ST2 axis is associated with radiation-induced cardiac injury.

Radiotherapy for treating breast cancer is associated with cardiac damage. This study aimed to investigate the role of the interleukin (IL)-33/soluble receptor ST2 (sST2) axis in radiation-induced cardiac injury. Expressions of IL-33 and sST2 were detected in breast cancer patients following radiotherapy, radiation-induced cardiac damaged mice model, and cardiomyocytes using quantitative real-time PCR (qRT-PCR) and immunohistochemical assay. Cardiac injury was evaluated through an ultrasound imaging system and hematoxylin & eosin staining. The transcriptional factor was assessed using dual-luciferase reporter assay and chromatin immunoprecipitation. The results indicated that IL-33 and sST2 were highly expressed in breast cancer patients, which further elevated post-6 months but reduced after 12 months of radiotherapy. Radiation induces cardiac dysfunction and elevated IL-33 and sST2 levels in a time-dependent manner. However, silencing of IL-33 decreased sST2 expression to alleviate radiation-induced cardiac dysfunction. The IL-33 could be transcriptional activated by TCF7L2 by binding to IL33 promoter sites, which mutation alleviated cardiomyocyte injury caused by radiation. Additionally, radiation treatment resulted in higher levels of TCF7L2, IL-33, and sST2 in cardiomyocytes, and TCF7L2 knockdown reduced IL-33 and sST2 expression. In conclusion, TCF7L2 transcriptional-activated IL-33 mediated sST2 to regulate radiation-induced cardiac damage, providing novel insights into radiotherapy-induced cardiac damage.

PAX1 represses canonical Wnt signaling pathway and plays dual roles during endoderm differentiation.

BACKGROUND: Paired box 1 (PAX1) is a transcription factor and essential for the development of pharyngeal pouches-derived tissues, including thymus. PAX1 mutations are identified in Severe Combined Immunodeficiency (SCID) patients with Otofaciocervical Syndrome Type 2 (OTFCS2). However, despite the critical roles of PAX1 in embryonic development and diseases, detailed insights into its molecular mode of action are critically missing. METHODS: The repressing roles of PAX1 and SCID associated mutants on Wnt signaling pathway were investigated by luciferase reporter assays, qRT-PCR and in situ hybridization in HEK293FT, HCT116 cells and zebrafish embryos, respectively. Co-immunoprecipitation (co-IP) and western blotting assays were carried out to identify the molecular mechanisms underlying PAX1's role on Wnt signaling pathway. hESC based endoderm differentiation, flow cytometry, high-throughput sequencing data analysis, and qRT-PCR assays were utilized to determine the roles of PAX1 during endoderm differentiation. RESULTS: Here, we show that PAX1 represses canonical Wnt signaling pathway in vertebrate cells. Mechanically, PAX1 competes with SUMO E3 ligase PIASy to bind to TCF7L2, thus perturbing TCF7L2 SUMOylation level, further reducing its transcriptional activity and protein stability. Moreover, we reveal that PAX1 plays dual roles in hESC-derived definitive and foregut/pharyngeal endoderm cells, which give rise to the thymus epithelium, by inhibiting Wnt signaling. Importantly, our data show PAX1 mutations found in SCID patients significantly compromise the suppressing ability of PAX1 on Wnt signaling. CONCLUSIONS: Our study presents a novel molecular mode of action of PAX1 in regulation of canonical Wnt signaling and endoderm differentiation, thus providing insights for the molecular basis of PAX1 associated SCID, offering better understanding of the behavior of PAX1 in embryogenesis.

TCF7L2 Polymorphism rs7903146 (C/T) and Gestational Diabetes Influence on Obstetric Outcome: A Romanian Case-Control Study.

Gestational diabetes mellitus (GDM) is one of the most frequent predictors of obstetric outcome among Romanian pregnant women. Thus, we aimed to investigate the role of rs7903146 (C/T) TCF7L2 gene polymorphism in the presence of GDM and to evaluate the influence on maternal-fetal outcomes in a cohort of pregnant women from Northern Transylvania. Our prospective case-control study was performed in a tertiary maternity center on 61 patients diagnosed with GDM and 55 normal pregnant patients. The patients were genotyped for rs7903146 (C/T) polymorphism of the TCF7L2 gene using the PCR-RFLP method between 24 and 28 weeks of gestation. The minor T allele was associated with a high risk of developing GDM (OR 1.71 [95% CI 0.82-3.59]) if both heterozygote and homozygote types were considered. Also, a higher risk of developing GDM was observed in homozygous carriers (OR 3.26 [95% CI 1.10-9.68]). Women with the TT genotype were more likely to require insulin therapy during pregnancy than other genotypes with a 5.67-fold increased risk ([1.61-19.97], p = 0.015). TT homozygote type was significantly associated with fetal macrosomia for birth weights greater than the 95th percentile (p = 0.034). The homozygous TT genotype is associated with an increased risk of developing GDM. Also, rs7903146 (C/T) TCF7L2 variant is accompanied by a high probability of developing insulin-dependent gestational diabetes mellitus (ID-GDM). The presence of at least one minor T allele was associated with a higher risk of fetal macrosomia.

Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus.

BACKGROUND: The genetic basis of type 2 diabetes (T2D) is under-investigated in the Middle East, despite the rapidly growing disease prevalence. We aimed to define the genetic determinants of T2D in Qatar. METHODS: Using whole genome sequencing of 11,436 participants (2765 T2D cases and 8671 controls) from the population-based Qatar Biobank (QBB), we conducted a genome-wide association study (GWAS) of T2D with and without body mass index (BMI) adjustment. RESULTS: We replicated 93 known T2D-associated loci in a BMI-unadjusted model, while 96 known loci were replicated in a BMI-adjusted model. The effect sizes and allele frequencies of replicated SNPs in the Qatari population generally concurred with those from European populations. We identified a locus specific to our cohort located between the APOBEC3H and CBX7 genes in the BMI-unadjusted model. Also, we performed a transethnic meta-analysis of our cohort with a previous GWAS on T2D in multi-ancestry individuals (180,834 T2D cases and 1,159,055 controls). One locus in DYNC2H1 gene reached genome-wide significance in the meta-analysis. Assessing polygenic risk scores derived from European- and multi-ancestries in the Qatari population showed higher predictive performance of the multi-ancestry panel compared to the European panel. CONCLUSION: Our study provides new insights into the genetic architecture of T2D in a Middle Eastern population and identifies genes that may be explored further for their involvement in T2D pathogenesis.

The effects of transcription factor 7-like 2 rs7903146 and paired box 4 rs2233580 variants associated with type 2 diabetes on the therapeutic efficacy of hypoglycemic agents.

Aim: This study aims to investigate the effects of the TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) variants associated with T2D on the therapeutic efficacies of various HAs in patients with T2D after follow-up for 3 years. Methods: A total of 526 patients who were followed up at the Diabetic Clinic of Siriraj Hospital during 2016-2019 were enrolled. The variants TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) were genotyped using the RNase H2 enzyme-based amplification (rhAmp) technique and the associations between genotypes and glycemic control after treatments with different combinations HA were evaluated using Generalized Estimating Equations (GEE) analysis. Results: Patients who carried TCF7L2 rs7903146C/T + T/T genotypes when they were treated with biguanide alone had significantly lower fasting plasma glucose (FPG) than those of the patients who carried the C/C genotype (p = 0.01). Patients who carried the PAX4 rs2233580 G/G genotype when they were treated with sulfonylurea alone had significantly lower FPG than those of the patients who carried G/A + A/A genotypes (p = 0.04). Conclusion: Genotypes of TCF7L2 rs7903146 and PAX4 rs2233580 (R192H) variants associated with T2D influence the therapeutic responses to biguanide and sulfonylurea. Different genotypes of these two variants might distinctively affect the therapeutic effects of HAs. This finding provides evidence of pharmacogenetics in the treatment of diabetes.

Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and ß-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

Haplotype-based association study of TCF7L2 gene variants with the development of diabetic retinopathy in an Iranian population.

BACKGROUND: Diabetic retinopathy (DR) is recognized as one of the most prevalent complications of diabetes and a major cause of morbidity. Transcription factor 7-like 2 (TCF7L2), a pivotal component in the Wnt-signaling pathway, plays a significant role in ß-cell development, blood-glucose homeostasis, cell survival, cell migration, and cell proliferation. Thus, this study aimed to assess the association between TCF7L2 variants (rs7903146, rs11196205, and rs12255372) with DR in a population-based association study. MATERIALS AND METHODS: DNA was extracted from whole blood of all subjects by salting-out procedure. Total 524 T2DM patients including 234 T2DM individuals without DR and 290 T2DM individuals with DR were genotyped by TaqMan assay technology. Clinical characteristics of subjects were conducted to evaluate the plausible association between TCF7L2 variants and DR with univariate linear regression analysis. RESULTS: Demographic analysis between case and control groups revealed significant differences in FBS, HbA1c, lipidemia, heart disease, and family history of T2DM (p < 0.05). No significant difference was observed in either genotypes distribution or allele frequency (p > 0.05) between T2DM individuals with and without DR in any models of inheritance. Genotype-phenotype association showed no significant association. Result of analysis indicated that HbAlc with adjusted OR of 1.8 (p < 0.0001) and first-degree relatives of family history with adjusted OR of 3.04 (p < 0.0001) were significantly associated with DR. Finally, haplotype analysis showed no noticeable association. CONCLUSION: In conclusion, there was no significant genetic association between rs7903146, rs11196205, and rs12255372 with DR among T2DM Iranians; however, these variants may play unknown roles in other populations.

Genetic Association of Transcription Factor 7-Like-2 rs7903146 Polymorphism With Type 2 Diabetes Mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) mainly results from the inability of muscle, fat, and liver cells to uptake glucose due to insulin resistance or deficiency of insulin production by the pancreas. Predisposition to T2DM may be due to environmental, hereditary, or both factors. Although there are many genes involved in causing T2DM, transcription factor 7-like-2 gene (TCF7L2) rs7903146 (C/T) single nucleotide polymorphism (SNP) found in genome-wide association studies (GWAS) is susceptible to T2DM. TCF7L2 is involved in pancreatic beta cell proliferation and differentiation via the Wnt signaling mechanism. OBJECTIVES: To find the genetic association of TCF7L2 rs7903146 (C/T) gene polymorphism in patients with T2DM. METHODS: A case-control study was conducted on 194 T2DM patients recruited from the endocrinology department at Indira Gandhi Institute of Medical Sciences, Patna, and 180 non-diabetic healthy controls that were age and sex-matched with the patients. All clinical examination and biochemical investigations like glycosylated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol; and determination of TCF7L2 gene polymorphism by allele-specific polymerase chain reaction (AS-PCR) were carried out for each subject. RESULTS:  The T allele of the rs7903146 (C/T) SNP was associated with a two-fold higher risk of T2DM and the heterozygous genotype (CT) with a 1.96 times higher risk. CONCLUSION: There is a high association of this SNP with the development of T2DM in the eastern Indian population. Serial monitoring of HbA1c should be done in an individual having this type of polymorphism for early detection of T2DM to prevent future complications.

Dbx1 is a dorsal midbrain-specific determinant of GABAergic neuron fate and regulates differentiation of the dorsal midbrain into the inferior and superior colliculi.

The mechanism underlying the differentiation of the dorsal midbrain into two morphologically and functionally distinct compartments, the inferior colliculus (IC) and superior colliculus (SC), which process auditory and visual information, respectively, remains largely unexplored. By using null and conditional alleles, we uncover the roles of a homeodomain transcription factor Dbx1 in the regulation of IC and SC differentiation. We show that Dbx1 regulates GABAergic neuron development in the dorsal midbrain. In the absence of Dbx1 function, the dorsal-most m1-m2 progenitor domains in the midbrain fail to activate GABAergic neuron-specific gene expression and instead switch to a glutamatergic phenotype. These results identify Dbx1 as a dorsal midbrain-specific GABAergic determinant that regulates the selector genes, Helt, Gata2, and Tal2. Furthermore, we demonstrate that maturation of the dorsal midbrain into the IC and SC is dependent on Dbx1. Null mutation of Dbx1 impairs the identity and fate of IC and SC neurons. Surprisingly, Dbx1 is required for preventing IC into SC fate switch and thus Dbx1-deficient IC neurons undergo acquisition of SC identity. Conditional inactivation of Dbx1 at late developmental phase leads to alteration in the identity and fate of the IC, but not the SC. These results suggest that SC differentiation is dependent on the early function of Dbx1, and that the IC requires the prolonged action for its normal formation. Furthermore, we uncover that Tcf7l2 acts downstream of Dbx1 selectively to promote IC differentiation. Altogether, our study identifies a molecular mechanism underlying spatial and temporal control of dorsal midbrain development.

TCF7L2 and FTO Polymorphisms Are Associated with Type 2 Diabetes Mellitus Risk in Kuwait.

OBJECTIVE: Despite the high prevalence of type 2 diabetes mellitus (T2DM) and obesity in the region, reports are limited on genetic risk factors associated with T2DM risk in Kuwait. Our aim was to investigate the association of reported FTO and TCF7L2 T2DM genetic risk variants in Kuwaiti T2DM patients. SUBJECTS AND METHODS: FTO rs9939609 and TCF7L2 rs7903146 variants were genotyped in 203 T2DM patients and 162 healthy controls. Data analysis included Fisher's exact test, χ2 test, and linear and logistic regression analyses. RESULTS: FTO rs9939609 (AA) and TCF7L2 rs7903146 (TT) genotypes associated with T2DM risk among Kuwaitis (p = 0.0016 and p < 0.0001; respectively). Both variants had the strongest association with T2DM risk in an autosomal recessive inheritance model (FTO rs9939609A: odds ratio (OR) 2.136, 95% confidence interval (CI): 1.21-3.67, p = 0.0075; TCF7L2 rs7903146T: OR 3.283, 95% CI: 1.92-5.76, p < 0.0001). Moreover, rs7903146T associated with risk of peripheral neuropathy (ß = 0.735, 95% CI: 0.514-0.96, p < 0.001) and risk of myocardial infarction (ß = 0.36, 95% CI: 0.024-0.7, p = 0.036) in T2DM patients. CONCLUSION: The increased susceptibility of Kuwaitis to T2DM is influenced by the same common genetic factors found in other T2DM populations. Further investigations of other T2DM genetic risk factors in Kuwait should refine and further support the clinical utility of a genetic risk score in predicting T2DM risk in a high-risk population such as Kuwait.

Correlation between TCF7L2 and CAPN10 gene polymorphisms and gestational diabetes mellitus in different geographical regions: a meta-analysis.

BACKGROUND: The association between TCF7L2 and CAPN10 gene polymorphisms and gestational diabetes mellitus (GDM) has been explored in diverse populations across different geographical regions. Yet, most of these studies have been confined to a limited number of loci, resulting in inconsistent findings. In this study, we conducted a comprehensive review of published literature to identify studies examining the relationship between TCF7L2 and CAPN10 gene polymorphisms and the incidence of GDM in various populations. We specifically focused on five loci that were extensively reported in a large number of publications and performed a meta-analysis. METHODS: We prioritized the selection of SNPs with well-documented correlations established in existing literature on GDM. We searched eight Chinese and English databases: Cochrane, Elton B. Stephens. Company (EBSCO), Embase, Scopus, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang, and China Science and Technology Journal Database and retrieved all relevant articles published between the inception of the database and July 2022. The Newcastle Ottawa Scale (NOS) was used to evaluate the selected articles, and the odds ratio (OR) was used as the combined effect size index to determine the association between genotypes, alleles, and GDM using different genetic models. Heterogeneity between the studies was quantified and the I2 value calculated. Due to large heterogeneities between different ethnic groups, subgroup analysis was used to explore the correlation between genetic polymorphisms and the incidence of GDM in the different populations. The stability of the results was assessed using sensitivity analysis. Begg's and Egger's tests were used to assess publication bias. RESULTS: A total of 39 articles reporting data on 8,795 cases and 16,290 controls were included in the analysis. The frequency of the rs7901695 genotype was statistically significant between cases and controls in the European population (OR = 0.72, 95% CI: 0.65-0.86) and the American population (OR = 0.61, 95% CI: 0.48-0.77). The frequencies of rs12255372, rs7901695, rs290487, and rs2975760 alleles were also considerably different between the cases and controls in the populations analyzed. CONCLUSIONS: rs7903146, rs12255372, rs7901695, rs290487, and rs2975760 were associated with the incidence of GDM in different populations.

Coronary artery disease patients with rs7904519 (TCF7L2) are at a persistent risk of type 2 diabetes.

AIMS: Type 2 diabetes (T2D) and coronary artery disease (CAD) often coexist and share genetic factors.This study aimed to investigate the common genetic factors underlying T2D and CAD in patients with CAD. METHODS: A three-step association approach was conducted: a) a discovery step involving 943 CAD patients with T2D and 1,149 CAD patients without T2D; b) an eliminating step to exclude CAD or T2D specific variants; and c) a replication step using the UK Biobank data. RESULTS: Ten genetic loci were associated with T2D in CAD patients. Three variants were specific to either CAD or T2D. Five variants lost significance after adjusting for covariates, while two SNPs remained associated with T2D in CAD patients (rs7904519*G: TCF7L2 and rs17608766*C: GOSR2). The T2D susceptibility rs7904519*G was associated with increased T2D risk, while the CAD susceptibility rs17608766*C was negatively associated with T2D in CAD patients. These associations were replicated in a UK Biobank data, confirming the results. CONCLUSIONS: No significant common T2D and CAD susceptibility genetic association was demonstrated indicating distinct disease pathways. However, CAD patients carrying the T2D susceptibility gene TCF7L2 remain at higher risk for developing T2D emphasizing the need for frequent monitoring in this subgroup.