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Background: Alopecia areata is an autoimmune disorder with a varied, typically relapsing or remitting nature. Numerous concomitant conditions, such as celiac, hypothyroidism, hyperlipidemia, type 1diabetes, and atherosclerosis, are linked to alopecia areata. Methods: This study was performed on (86) subjects who were categorized into two groups; Group (1): included 43 healthy individuals. Group (2): included 43 patients diagnosed with alopecia areata. This group was divided into 2 groups; group A: 20 patients were treated by conventional therapy. Group B: 23 patients were treated by Platelet Rich Plasma (PRP) (local intradermal injection). Whole blood samples were used for genotyping of TCF7L2 polymorphisms (rs7903146). Results: Regarding TCF7L2 genotyping: CT, TT, and CT+TT genotypes of TCF7L2 were significantly higher in cases compared to controls. There was no significant difference between different TCF7L2 genotypes among alopecia patients regarding to demographic data and Clinical findings except white hair before treatment. There was no significant variation between different TCF7L2 genotypes in PRP and steroid-treated alopecia patients regarding demographic data and clinical findings except exclamation mark in PRP treated group. Conclusions: TCF7L2 gens polymorphismis associated with alopecia areata, however, there was no significant difference between PRP treatment and conventional therapy regarding the different genotypes. [ABSTRACT FROM AUTHOR]

Background: Transcription factor 7-like 2 (TCF7L2) variants seem to affect diabetes susceptibility through β-cell dysfunction, underlying basis of which has been considered to be β-cell dedifferentiation rather than apoptotic β-cell death. The Extracellular regulated protein kinases/Mitogen-activated protein kinase signaling pathway (ERK/MAPK signaling pathway) has been confirmed to be significantly associated with multiple cellular process, including cellular dedifferentiation. However, the effects of TCF7L2 on β-cell function and ERK/MAPK signaling pathway are poorly understood. Objectives: This study aimed to elucidate the regulation of TCF7L2 in β-cell function and ERK/MAPK signaling pathway, which further participate in glucose metabolism and diabetes progression. Methods: After transfection of TCF7L2 siRNA and lenti-TCF7L2 plasmids, the activation of ERK/MAPK signaling and β-cell dedifferentiation were evaluated respectively. Six week-old male db / db mice were randomly grouped and fed a normal or high-fat diet, and then pancreatic level of TCF7L2 protein were measured respectively when the mice were fed to 8, 12, and 16 weeks of age. Furthermore, the contributions of TCF7L2 to ERK/MAPK signaling and glucose metabolism were investigated in a β-cell-specific TCF7L2 deletion mice model (TCF7L2β−/−). Results: The results demonstrated that impaired TCF7L2 induces β-cell dedifferentiation and decreases insulin secretion of MIN6 cells via ERK/MAPK signaling pathway. Consistently, decreased pancreatic TCF7L2 protein in parallel with reduced functional β-cells were observed in db / db mice after weeks of normal or high-fat diet. However, the differences between were only significant when the mice were fed to 12 weeks of age. After weeks of high-fat diet feeding, impaired glucose tolerance and increased activation of ERK/MAPK signaling were simultaneously observed in TCF7L2β−/− mice. Conclusion: The study indicate that the induction of β-cell dedifferentiation mediated by ERK/MAPK signaling pathway might be an essential component of TCF7L2 variants in the development of diabetes. Plain Language Summary: Inhibitory effect of TCF7L2 on pancreatic β-cell dedifferentiation via ERK/MAPK signaling pathway in diabetes Transcription factor 7-like 2 (TCF7L2) variants seem to affect diabetes susceptibility through β-cell dysfunction, underlying basis of which has been considered to be β-cell dedifferentiation rather than apoptotic β-cell death. Nowadays, how TCF7L2 participates in β-cell dedifferentiation and how pancreatic TCF7L2 protein changes during diabetes progression are poorly understood. The Extracellular regulated protein kinases/Mitogen-activated protein kinase signaling pathway (ERK/MAPK signaling pathway) has been confirmed to be significantly associated with multiple cellular process, including cellular dedifferentiation. Here, we demonstrated that impaired TCF7L2 induces β-cell dedifferentiation and decreases insulin secretion of MIN6 cells via ERK/MAPK signaling pathway. Consistently, declined pancreatic TCF7L2 protein in parallel with reduced mature β-cells were observed in db / db mice after weeks of normal or high-fat diet feeding. Furthermore, the role of TCF7L2 in dedifferentiation and glucose homeostasis were validated in mice with β cell-specific TCF7L2 deletion (TCF7L2β−/−). In conclusion, the study indicate that the induction of β-cell dedifferentiation mediated by ERK/MAPK signaling pathway might be an essential component of TCF7L2 variants in the development of diabetes. [ABSTRACT FROM AUTHOR]

Background: The metabolic syndrome consists of a combination of metabolic abnormalities and genetic predisposition that both contribute significantly to its development. Numerous studies have established a strong association between single nucleotide polymorphisms (SNPs) of the rs7903146 variant in the TCF7L2 gene and the metabolic syndrome (MetS) as well as type 2 diabetes. Objective: The aim of this study was to assess the impact of rs7903146 on MetS and its components. Methods: For this cross-sectional study, 325 individuals aged 25 to 86 who were selected from the baseline data of the Ahvaz cohort study were examined. Body mass index, blood pressure, fasting blood glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured following standard protocols. MetS subjects were identified based on the National Cholesterol Education Program guidelines. Genotyping was conducted using the PCR-RFLP method. Results: Our findings revealed that individuals with the CT genotype of rs7903146 had an increased risk of MetS (OR 2.24; 95% CI, 1.26–3.98; p < 0.006). This genotype was also found to be associated with a higher risk of hypertension and low HDL cholesterol (p < 0.05). Moreover, plasma triglyceride levels were slightly higher in individuals with TT and CT genotypes, although not significantly so (p = 0.06). Conclusion: In conclusion, the CT genotype of the TCF7L2 rs7903146 polymorphism exhibited higher odds for MetS. While lifestyle factors and other genes are also implicated in MetS, our findings suggest that studying TCF7L2 polymorphisms in high-risk groups could contribute to the development of genotype-specific prevention or treatment strategies. However, further research is required to validate these results. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

Abstract 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.

الملخص: أهداف البحث: يعتبر جين ''عامل الانتساخ 7-مثل 2'' من الجينات المهمة التي وجد أنها مرتبطة بالاستعداد لمرض السكري من النوع الثاني في مختلف المجموعات العرقية. هدف هذا البحث هو التحقيق في العلاقة بين التعبير الجيني جين ''عامل الانتساخ 7-مثل 2'' وعدة مؤشرات كيميائية حيوية بين فئات عمرية مختلفة من مرضى السكري من النوع الثاني في عينة من السكان العراقيين. طرق البحث: تم جمع 150 عينة دم بالتساوي من 3 مجموعات: مرضى السكري من النوع الثاني الشباب (10-35 سنة)، مرضى السكري من النوع الثاني المسنين (40-80 سنة)، ومجموعة ضابطة صحية (10-65 سنة). تم إشراك كلا الجنسين. تم إجراء تفاعل البلمرة المتسلسل في الوقت الفعلي لاستكشاف التعبير الجيني جين ''عامل الانتساخ 7-مثل 2''. تم إجراء الاختبارات الكيميائية الحيوية: نسبة الهيموجلوبين السكري، والدهون الثلاثية، والبروتين الدهني منخفض الكثافة، والبروتين الدهني عالي الكثافة. تم احتساب مؤشر كتلة الجسم. تم تحليل النتائج إحصائيا. النتائج: كان لدى مرضى السكري من النوع الثاني سجلات أعلى فيما يتعلق بمؤشر كتلة الجسم، والدهون الثلاثية، والبروتين الدهني منخفض الكثافة، ونتائج البروتين الدهني عالي الكثافة أقل من مجموعة الضبط. هناك ارتباط إيجابي قوي بين نسبة الهيموجلوبين السكري ومؤشر كتلة الجسم، والدهون الثلاثية، والبروتين الدهني منخفض الكثافة. كان هناك ارتباط سلبي بين نسبة الهيموجلوبين السكري والبروتين الدهني عالي الكثافة. أظهر التعبير الجيني جين ''عامل الانتساخ 7-مثل 2'' اختلافا كبيرا بين المرضى المسنين والشباب بنسبة 1.68 و 0.207 على التوالي. أظهرت هذه النتائج أن المرضى المسنين لديهم تعبير جيني أعلى مقارنة بالمرضى الشباب. الاستنتاجات: تأثر التعبير الجيني جين ''عامل الانتساخ 7-مثل 2 ''بالعمر، وكانت السجلات الأعلى للمرضى المسنين من النوع الثاني من السكري. قد يؤثر ذلك على وظائف خلايا بيتا وإفراز الأنسولين. Abstract: 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.

Oligodendrocyte progenitor cells (OPCs) differentiation into oligodendrocytes (OLs) and subsequent myelination are two closely coordinated yet differentially regulated steps for myelin formation and repair in the CNS. Previously thought as an inhibitory factor by activating Wnt/beta‐catenin signaling, we and others have demonstrated that the Transcription factor 7‐like 2 (TCF7l2) promotes OL differentiation independent of Wnt/beta‐catenin signaling activation. However, it remains elusive if TCF7l2 directly controls CNS myelination separating from its role in upstream oligodendrocyte differentiation. This is partially because of the lack of genetic animal models that could tease out CNS myelination from upstream OL differentiation. Here, we report that constitutively depleting TCF7l2 transiently inhibited oligodendrocyte differentiation during early postnatal development, but it impaired CNS myelination in the long term in adult mice. Using time‐conditional and developmental‐stage‐specific genetic approaches, we further showed that depleting TCF7l2 in already differentiated OLs did not impact myelin protein gene expression nor oligodendroglial populations, instead, it perturbed CNS myelination in the adult. Therefore, our data convincingly demonstrate the crucial role of TCF7l2 in regulating CNS myelination independent of its role in upstream oligodendrocyte differentiation. [ABSTRACT FROM AUTHOR]

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, β-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 β-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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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Abstract 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.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

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 (β = 0.735, 95% CI: 0.514–0.96, p < 0.001) and risk of myocardial infarction (β = 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. Highlights of the Study: FTO variant rs9939609A is associated with an increased risk of obesity but not of type 2 diabetes, among Kuwaitis. TCF7L2 rs7903146T variant is associated with an increased risk of type 2 diabetes mellitus among Kuwaitis. [ABSTRACT FROM AUTHOR]

The genetic etiology of gestational diabetes mellitus (GDM) was suggested to overlap with type-2 diabetes(T2D). Transcription factor 7-like 2 (TCF7L2) and Proprotein Convertase Subtilisin/Kexin type 2 (PCSK2) are T2D susceptibility genes of the insulin synthesis/processing pathway. We analyzed associations of TCF7L2 and PCSK2 variants with GDM risk and evaluated their potential impact on impaired insulin processing in an eastern Indian population. The study included 114 GDM (case) and 228 non-GDM pregnant women (control). rs7903146, rs4132670, rs12255372 of TCF7L2, and rs2269023 of PCSK2 were genotyped by PCR-RFLP, and genotype distributions were compared between case and control. Fasting serum proinsulin and C-peptide levels were measured by ELISA and the Proinsulin/C-peptide ratio was considered an indicator of proinsulin conversion. Significantly higher frequency of risk allele (T) of rs12255372 (p = 0.02, OR = 2.0, 95%CI = 1.11–3.64) and rs4132670 (p = 0.002, OR = 2.26, 95%CI = 1.32–3.87) of TCF7L2 was found in GDM cases than non-GDM controls; TT genotype was associated with significantly increased disease risk. In rs7903146 (TCF7L2) and rs2269023 (PCSK2), although the frequency of risk allele (T) was not significantly higher in cases than controls, an association of TT for both variants remained significant with higher GDM risk in the recessive model. Increased serum pro-insulin and proinsulin:c-peptide ratio was found in GDM than non-GDM women and the phenomenon showed significant association with careers of risk alleles for TCF7L2 variants. In conclusion, TCF7L2 and PCSK2 variants are related to GDM risk in the studied population and hence may serve as potential biomarkers for assessing the disease risk. TCF7L2 variants contribute to impaired insulin processing. [ABSTRACT FROM AUTHOR]

We have read with interest the article entitled “A Cross-sectional Study to Evaluate Beta Cell Function in Individuals with Newly Diagnosed Young-Onset Type 2 Diabetes Mellitus and its Complications,”1 elevated C-peptide levels are indicative of both insulin resistance and beta cell malfunction. These factors are directly linked to the development of complications associated with young-onset Type 2 Diabetes Mellitus (YO-T2DM), including obesity, hypertension, and diabetic kidney disease. The present letter aims to expand the current diagnostic testing options for early detection of YO-T2DM.

Abstract 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 I 2 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.

The review addresses publications on genetic polymorphisms that potentially impact the effectiveness of therapy with hypoglycemic drugs of the dipeptidyl peptidase-4 inhibitor group. The literature was searched in the PubMed database from 2017 to 2023. Polymorphisms of several genes (GLP1R, TCF7L2, DPP-4, KCNQ1, KCNJ11, PNPLA3, PRKD1) are associated with the pharmacokinetic values and efficacy of dipeptidyl peptidase-4 inhibitors, which may be promising for personalizing the treatment of patients with type 2 diabetes mellitus.

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 dorsalmost 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. [ABSTRACT FROM AUTHOR]

The transcription factor promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16) is critical for the self-renewal of spermatogonial stem cells (SSCs). However, the function of PLZF in SSCs is not clear. Here, we found that PLZF acted as an epigenetic regulator of stem cell maintenance and self-renewal of germ cells. The PLZF protein interacts with the ten-eleven translocation 1 (TET1) protein and subsequently acts as a modulator to regulate the expression of self-renewal-related genes. Furthermore, Transcription Factor 7-like 2 (TCF7L2) is promoted by the coordination of PLZF and Tri-methylation of lysine 4 on histone H3 (H3K4me3). In addition, testicular single-cell sequencing indicated that TCF7L2 is commonly expressed in the PLZF cluster. We demonstrated that PLZF directly targets TCF7L2 and alters the landscape of histone methylation in the SSCs nucleus. Meanwhile, the RD domain and Zn finger domain of PLZF synergize with H3K4me3 and directly upregulate TCF7L2 expression at the transcriptional level. Additionally, we identified a new association between PLZF and the histone methyltransferase EZH2 at the genomic level. Our study identified a new association between PLZF and H3K4me3, established the novel PLZF&TET1-H3K4me3-TCF7L2 axis at the genomic level which regulates undifferentiated spermatogonia, and provided a platform for studying germ cell development in male domestic animals. • PLZF interacts with TET1 protein to act as a transcriptional activator in SSCs. • PLZF is conserved in mammals and is highly expressed in CD49f positive cells jointly with TCF4. • The transcription factor PLZF directly targets TCF7L2, which is an effector of wnt signaling. • PLZF synergies with H3K4me3 to directly target TCF4 in undifferentiated spermatogonial stem cells. • The role of RD2 domain of PLZF in transcriptional regulation was analyzed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Abstract Patients with chronic liver disease (CLD) as chronic hepatitis C (CHC) are at high risk of diabetes type 2 (T2D). Genetic factors are suggested to modulate diabetes development in cirrhotic patients. TCF7L2 gene has been reported to be associated with type 2 diabetes, but the association of TCF7L2 with cirrhotic patients with diabetes is unclear. We aimed to study the TCF7L2 gene polymorphisms (rs 290487) in cirrhotic patients with diabetes. Method The study was assessed on 25 cirrhotic patients with type 2 diabetes who were compared to 25 cirrhotic HCV patients (nondiabetic), 25 diabetic type 2 patients, and 25 age- and gender-matched healthy control groups. After the collection of relevant clinical data and basic laboratory tests, single-nucleotide polymorphism (SNP) in the TCF7L2 gene (rs290487) was performed by a real-time PCR technique. Results Cirrhotic patients with diabetes presented significantly poorer liver function, higher incidence of cirrhotic complications, and higher glucose levels compared with cirrhotic nondiabetic patients. The TCF7L2 rs290487 TT variant showed significantly increased diabetes risk in cirrhotic patients compared with CC and CT genotypes. Conclusions TCF7L2 rs290487 polymorphism could be associated with increased diabetic risk in cirrhotic patients.

Objective: Gestational Diabetes Mellitus (GDM) is one of the most common complications of pregnancy and becoming an increasing health problem worldwide. The rate of GDM is increasing in Asian countries including Bangladesh. This study is aimed at investigating the association between the rs12255372 (G/T) polymorphism of the TCF7L2 gene with GDM. Method: To carry out the present research, 63 GDM pregnant women and 60 control pregnant women were randomly selected from the city Chattogram, Bangladesh. During the study data was collected between gestational weeks of 24–28. PCR-RFLP was used for genotyping the rs12253372 (G/T) and for genotype analysis Hardy-Weinberg equation (Hardy, 1908) was applied. Results: The fasting and 2-hour plasma glucose level was significantly higher in GDM than the control. Moreover, in the case of family history women with GDM showed higher percentage in first degree relatives (60.31 %) compared to that of control (38.33 %). The frequency of mutant allele T in GDM is 26.2 % which was however not significant. TT genotype was found only in one subject with GDM. However, the percentage of risk allele GT is higher in GDM (49.2 %) compared to that of NGT (35 %). Conclusions: In our pilot study, we did not find an association between rs12255372 (G/T) polymorphism of TCF7L2 gene and GDM. Studying in a broader group may help to find a conclusive result.

Patients with chronic liver disease (CLD) as chronic hepatitis C (CHC) are at high risk of diabetes type 2 (T2D). Genetic factors are suggested to modulate diabetes development in cirrhotic patients. TCF7L2 gene has been reported to be associated with type 2 diabetes, but the association of TCF7L2 with cirrhotic patients with diabetes is unclear. We aimed to study the TCF7L2 gene polymorphisms (rs 290487) in cirrhotic patients with diabetes. Method The study was assessed on 25 cirrhotic patients with type 2 diabetes who were compared to 25 cirrhotic HCV patients (nondiabetic), 25 diabetic type 2 patients, and 25 age- and gender-matched healthy control groups. After the collection of relevant clinical data and basic laboratory tests, single-nucleotide polymorphism (SNP) in the TCF7L2 gene (rs290487) was performed by a real-time PCR technique. Results Cirrhotic patients with diabetes presented significantly poorer liver function, higher incidence of cirrhotic complications, and higher glucose levels compared with cirrhotic nondiabetic patients. The TCF7L2 rs290487 TT variant showed significantly increased diabetes risk in cirrhotic patients compared with CC and CT genotypes. Conclusions TCF7L2 rs290487 polymorphism could be associated with increased diabetic risk in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Background: Rotational night shift work has been shown to be associated with increased risk of diabetes. However, the exact mechanism is not clear. The present study aimed to investigate the expression of TCF7L2 and PPAR-γ genes in healthcare workers with normal glucose tolerance performing rotational night shift duties. Methods: The expression of TCF7L2 and PPAR-γ genes in peripheral blood was compared in two groups (n = 20 each group) of healthcare workers with normal glucose tolerance (NGT). The first group included NGT healthcare workers performing rotational night shift duties. The second group included NGT healthcare workers performing regular day shifts. Blood samples in the study group were collected 1 week after the last night shift to document the long-term effects of night shift work on the expression of TCF7L2 and PPAR-γ genes. Results: The age of study participants in the first group was 29.7 ± 3.92 and in the second group was 29.7 ± 2.23 years. Body mass index was 23.69 ± 2.59 and 24.35 ± 2.82 kg/m2 in both groups, respectively (p = 0.4). The expression of TCF7L2 gene was found to be 4.6-fold increased in NGT healthcare workers performing rotational night shift duties compared to those performing day shift duties (p = 0.02). The expression of PPAR-γ gene was found to be 3.7-fold decreased in NGT healthcare workers performing rotational night shift duties compared to those performing day shift duties (p = 0.04). The mean duration of exposure to rotational night shift work was 4.6 years. Conclusion: Rotational night shift work adversely affects the expression of common diabetogenic genes TCF7L2 and PPAR-γ in healthcare workers with normal glucose tolerance. This suggests a possible role for the dysregulation of these genes in shift work associated diabetes risk. [ABSTRACT FROM AUTHOR]

Polymorphism of transcription factor 7-like 2 (TCF7L2) has a link with type 2 diabetes mellitus (T2DM) through β cell dysfunction that causes defect in blood glucose homeostasis. This case–control study recruited 67 T2DM as cases and 65 age-matched healthy individuals as controls to determine whether the polymorphism rs12255372 (G > T) in the TCF7L2 gene have an association with T2DM in Bangladeshi population. Genomic DNA was purified from peripheral whole blood sample and direct Sanger sequencing was done for genotyping of SNP. Bivariate logistic regression was done to find out the association between genetic variant and T2DM. In our study, the minor T allele frequency was significantly more frequent in T2DM group than healthy controls (29.1% vs. 16.9%). After adjusting with confounding factors, heterozygous-genotype GT had higher odds of developing T2DM (OR 2.4; 95% CI: 1.0–5.5; p value = 0.04) and in dominant model, having SNP in TCF7L2 increased the risk of T2DM 2.3 times (95% CI: 1.0–5.2; p value = 0.04). In interaction model, genetic susceptible SNP cases interacted significantly with increasing age and BMI, female gender, and having family history of diabetes mellitus to develop T2DM (pinteraction < 0.001). Having minor T allele either in heterozygous or homozygous variant form of rs12255372 (G > T) TCF7L2 had significant association with T2DM. In conclusion, TCF7L2 gene variant increases risk of developing T2DM among the Bangladeshi population. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Transcription factor 7-like 2 (TCF7L2) gene variants confer risk for type 2 diabetes and metabolic traits. We investigated the role of TCF7L2-variants in polycystic ovarian syndrome (PCOS), which is a common endocrine metabolic disorder affecting women of reproductive age. We tested whether TCF7L2 variants are in linkage to and/or in linkage disequilibrium [(LD), namely linkage and association)] with PCOS. PATIENTS AND METHODS: Within 212 families from the Italian peninsular population, we analyzed 78 variants using Pseudomarker software for linkage to and LD with PCOS under the dominant model with complete penetrance (D1). In a secondary analysis, we tested the variants under the recessive models with complete penetrance (R1), dominant with incomplete penetrance (D2), and recessive with incomplete penetrance (R2). We tested through in silico analysis the risk variants to detect any potential functional effects. RESULTS: We identified a total of 14 variants in the TCF7L2 gene significantly linked to and/or in LD with the risk of PCOS (p < 0.05) across different models. CONCLUSIONS: This study is the first to report TCF7L2 linkage and linkage disequilibrium in Italian families with PCOS. [ABSTRACT FROM AUTHOR]

Background: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition involving various genetic and environmental factors leading to impaired insulin secretion, resulting in hyperglycemia. The transcription factor 7-like 2 (TCF7L2) gene is an element of the Wnt signaling pathway that plays an important role in glucose and lipid metabolism. The aim of this study is to evaluate the association of TCF7L2 rs7903146 and rs12255372 polymorphisms in T2DM with hypertriglyceridemia. Methods: We investigated the effect of rs7903146 and rs12255372 on T2DM with high triglyceride (TG) levels in 60 patients and 20 controls. The anthropometric measurements and biochemical tests were assessed. Peripheral blood samples were collected, and genomic DNA was extracted. The genotyping of TCF7L2 polymorphisms was carried out using polymerase chain reaction (PCR)-based direct sequencing and allele-specific PCR methods. The T2DM patients and controls were compared by means of the t-test, Chi-square test, odds ratio (OR), and 95% confidence interval (CI) using Epi Info v7. Results: The HbA1c was found to be 9.7 ± 2.1 and 5.4 ± 0.5% in patients and controls, respectively. The average TG levels (P < 0.005) in patients were 205.2 ± 145.7 and 106.4 ± 27.4mg/dl in controls. Significant evidence of association was found in T2DM patients having high TG levels with rs7903146 CT/TT (OR: 4.89; P = 0.0105) and rs12255372 GT/TT (OR: 5.23; P = 0.0101) genotypes when compared to controls. Conclusion: The results of this study show that TCF7L2 rs7903146 CT/TT and rs12255372 GT/TT genotypes are significantly associated with the risk of hypertriglyceridemia in individuals with T2DM among the studied population. [ABSTRACT FROM AUTHOR]

Objective. Nowadays, type 2 diabetes mellitus (T2D) is the most common chronic endocrine disorder affecting an estimated 5–10% of adults worldwide, and this disease also rapidly increased among the population in the Kurdistan region. This research aims to identify DNA methylation change in the TCF7L2 gene as a possible predictive T2D biomarker.

Abstract Background Among candidate genes related to type 2 diabetes (T2DM), one of the strongest genes is Transcription factor 7 like 2 (TCF7L2), regarding the Genome-Wide Association Studies. We aimed to conduct a systematic review of the literature on the modification effect of TCF7L2 on the relation between glycemic parameters and lifestyle factors. Methods A systematic literature search was done for relevant publications using electronic databases, including PubMed, EMBASE, Scopus, and Web of Science, from January 1, 2000, to November 2, 2021. Results Thirty-eight studies (16 observational studies, six meal test trials, and 16 randomized controlled trials (RCTs)) were included. Most observational studies had been conducted on participants with non-diabetes showing that TCF7L2 modified the association between diet (fatty acids and fiber) and insulin resistance. In addition, findings from meal test trials showed that, compared to non-risk-allele carriers, consumption of meals with different percentages of total dietary fat in healthy risk-allele carriers increased glucose concentrations and impaired insulin sensitivity. However, ten RCTs, with intervention periods of less than ten weeks and more than one year, showed that TCF7L2 did not modify glycemic parameters in response to a dietary intervention involving different macronutrients. However, two weight loss dietary RCTs with more than 1-year duration showed that serum glucose and insulin levels decreased and insulin resistance improved in non-risk allele subjects with overweight/obesity. Regarding artichoke extract supplementation (ALE), two RCTs observed that ALE supplementation significantly decreased insulin concentration and improved insulin resistance in the TT genotype of the rs7903146 variant of TCF7L2. In addition, four studies suggested that physical activity levels and smoking status modified the association between TCF7L2 and glycemic parameters. However, three studies observed no effect of TCF7L2 on glycemic parameters in participants with different levels of physical activity and smoking status. Conclusion The modification effects of TCF7L2 on the relation between the lifestyle factors (diet, physical activity, and smoking status) and glycemic parameters were contradictory. PROSPERO registration number CRD42020196327

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) associated with type 2 diabetes may more easily progress towards severe forms of non-alcoholic steatohepatitis (NASH) and cirrhosis. Although the Wnt effector transcription factor 7-like 2 (TCF7L2) is closely associated with type 2 diabetes risk, the role of TCF7L2 in NAFLD development remains unclear. Here, we investigated how changes in TCF7L2 expression in the liver affects hepatic lipid metabolism based on the major risk factors of NAFLD development. Methods: Tcf7l2 was selectively ablated in the liver of C57BL/6N mice by inducing the albumin (Alb) promoter to recombine Tcf7l2 alleles floxed at exon 5 (liver-specific Tcf7l2-knockout [KO] mice: Alb-Cre;Tcf7l2f/f). Alb-Cre;Tcf7l2f/f and their wild-type (Tcf7l2f/f) littermates were fed a high-fat diet (HFD) or a high-carbohydrate diet (HCD) for 22 weeks to reproduce NAFLD/NASH. Mice were refed a standard chow diet or an HCD to stimulate de novo lipogenesis (DNL) or fed an HFD to provide exogenous fatty acids. We analysed glucose and insulin sensitivity, metabolic respiration, mRNA expression profiles, hepatic triglyceride (TG), hepatic DNL, selected hepatic metabolites, selected plasma metabolites and liver histology. Results: Alb-Cre;Tcf7l2f/f essentially exhibited increased lipogenic genes, but there were no changes in hepatic lipid content in mice fed a normal chow diet. However, following 22 weeks of diet-induced NAFLD/NASH conditions, liver steatosis was exacerbated owing to preferential metabolism of carbohydrate over fat. Indeed, hepatic Tcf7l2 deficiency enhanced liver lipid content in a manner that was dependent on the duration and amount of exposure to carbohydrates, owing to cell-autonomous increases in hepatic DNL. Mechanistically, TCF7L2 regulated the transcriptional activity of Mlxipl (also known as ChREBP) by modulating O-GlcNAcylation and protein content of carbohydrate response element binding protein (ChREBP), and targeted Srebf1 (also called SREBP1) via miRNA (miR)-33-5p in hepatocytes. Eventually, restoring TCF7L2 expression at the physiological level in the liver of Alb-Cre;Tcf7l2f/f mice alleviated liver steatosis without altering body composition under both acute and chronic HCD conditions. Conclusions/interpretation: In mice, loss of hepatic Tcf7l2 contributes to liver steatosis by inducing preferential metabolism of carbohydrates via DNL activation. Therefore, TCF7L2 could be a promising regulator of the NAFLD associated with high-carbohydrate diets and diabetes since TCF7L2 deficiency may lead to development of NAFLD by promoting utilisation of excess glucose pools through activating DNL. Data availability: RNA-sequencing data have been deposited into the NCBI GEO under the accession number GSE162449 (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162449). [ABSTRACT FROM AUTHOR]

Abstract Background TCF7L2 rs7903146 and PNPLA3 rs738409 gene variants confer the strongest risk for type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD), respectively. Pancreatic triacylglycerol content (PTGC) was reported to have a role in T2DM development. We aimed to assess the correlation between PTGC and hepatic triacylglycerol content (HTGC) stratified by PNPLA3 rs738409 genotype and subsequently interactions between PTGC and gene variants associated with β-cell dysfunction (TCF7L2, WFS1) and visceral adiposity (11ΒHSD1) on β-cell function were also tested. Methods PTGC and HTGC were assessed using MR in a post-hoc analysis of a genotype-based (PNPLA3 rs738409) recall study of 39 (lipid- and glucose lowering) drug-naïve women. Oral glucose tolerance test, HbA1c, insulin indices, anthropometric data were evaluated. The effect of minor allele carrying of TCF7L2 (rs7903146); WFS1 (rs1801214) and 11ΒHSD1 (rs4844880) variants in combination with PTGC was studied on surrogate markers of β-cell function. We used Spearman’s rank-order, Mann-Whitney-U tests, and linear regression models. Results PTGC and HTGC values were correlated after stratification by the rs738409 variant (only in CC genotype group R = 0.67, p = 10− 4). PTGC and HbA1c values correlated in the entire study population (R = 0.58, p = 10− 4). Insulin resistance, sensitivity and disposition indices were correlated with PTGC (HOMA2-IR: R = 0.42, p = 0.008; TyG: R = 0.38, p = 0.018; Matsuda: R= − 0.48, p = 0.002; DIbasal: R=−0.33, p = 0.039; ISSI-2: R=−0.35, p = 0.028). Surrogate markers of β-cell function (HOMA2-B, AUCinsulin/AUCglucose) correlated significantly with PTGC in subjects with the following genotypes rs7903146: CC R = 0.51, p = 0.022; rs18001214: CT + CC R = 0.55, p = 0.013; rs4844880: TA + AA R = 0.56, p = 0.016. The strongest interactions were found between PTGC and TCF7L2 rs7903146 effect on HOMA2-B (p = 0.001) and AUCinsulin/AUCglucose (p = 0.013). Conclusions The PNPLA3 rs738409 genotype has a major effect on the correlation between PTGC and HTGC. Furthermore we first report the combined effect of PTGC and individual risk gene variants of TCF7L2, WFS1 and 11ΒHSD1 on β-cell dysfunction. The correlation between pancreatic lipid accumulation and HbA1c also indicates an important role for the latter pathology.

OBJECTIVE: Alterations in the activity of the transcription factor 7-like 2 (TCF7L2) generate defects previously associated with neuropsychiatric disorders. We investigated the role of the TCF7L2 gene in major depressive disorder (MDD), type 2 diabetes (T2D), and MDD-T2D comorbidity. We tested whether TCF7L2 is in linkage to and/or in linkage disequilibrium (LD, namely association) with MDD, T2D, and MDD-T2D. PATIENTS AND METHODS: In 212 families with T2D and MDD in the Italian population, we analyzed 80 microarray-based SNPs using Pseudomarker software for linkage to and LD with T2D and MDD under the recessive model with complete penetrance (R1). In a secondary analysis, we tested the variants under the dominant models with complete penetrance (D1), recessive with incomplete penetrance (R2), and recessive with incomplete penetrance (R2). RESULTS: We found several novel linkage signals and genetic associations. In addition, we found two new transcription-factor (TF) binding sites created by two risk variants found: the MDD-risk variant rs12255179 creates a new TF-binding site for the CCAAT/enhancer-binding protein α (C/EBPα), and the T2D-risk variant rs61872794 creates a new TF-binding site for the organic cation-uptake transporter (OCT1). Both new binding sites are related to insulin metabolism. CONCLUSIONS: These results highlight the cross-interactivity between T2D and MDD. Further replication is needed in diverse ethnic groups. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a severe health burden for Bangladesh. Genetic polymorphism has been reported to be one of the major risk factors for diabetes in various studies. TCF7L2 (transcription factor 7 like 2) transcripts in the human β-cell have effects on β-cell survival, function, and Wnt signaling activation. This study aimed to evaluate the frequency and association of various polymorphisms namely TCF7L2 rs12255372 and rs7903146 among Bangladeshi patients with T2DM (Type 2 Diabetes Mellitus). Methods: This case–control study included 300 patients with T2DM and 234 healthy individuals from two health facilities in the Chattogram Division of Bangladesh. Anthropometric measurements were assessed using a self-reported, structured, eight-item questionnaire. The polymorphisms were identified by PCR–RFLP and sequencing method. Results: A strong association of T2DM with polymorphisms was observed, including rs12255372 (p = 0.0004) and rs7903146 (p = 0.005). It was observed that the risk genotype at rs12255372 was associated with age (p = 0.009), a family history of diabetes (p < 0.0001), and HbA1C (p < 0.0001). Furthermore, it was found that rs12255372 was substantially associated with hypertension (p = 0.03), eye problems (p = 0.01), and neurological abnormalities (p = 0.02). Conclusion: This study postulates that TCF7L2 genetic polymorphism is associated with the risk of T2DM among the studied Bangladeshi population. The findings should be replicated through more studies with a large number of samples and in different populations. [ABSTRACT FROM AUTHOR]

This study investigates the antidiabetic and antioxidant potential of chitosan-encapsulated selenium nanoparticles in streptozotocin-induced diabetic model. Glibenclamide was used as a reference antidiabetic drug. Forty-eight adult male Wistar rats were used along the study and divided equally into 6 groups of (I) normal control, (II) chitosan-encapsulated selenium nanoparticles (CTS-SeNPs), (III) glibenclamide, (IV) streptozotocin (STZ), (V) STZ + CTS-SeNPs, and (VI) STZ + Glib. The animals were sacrificed on the 35th day of the experiment. Serum glucose, insulin, IGF-1, ALT, AST, CK-MB, oxidative stress, lipid profile, and inflammatory parameters were subsequently assessed. Also, the expression level of TCF7L2, CAPN10, and PPAR-γ genes were evaluated using qPCR. In addition, histopathological studies on pancreatic tissue were carried out. The results revealed that STZ induced both diabetes and oxidative stress in normal rats, manifested by the significant changes in the studied parameters and in the physical structure of pancreatic tissue. Oral administration of CTS-SeNPs or Glib results in a significant amelioration of the levels of serum fasting blood glucose, insulin, IGF-1, AST, ATL, and CK-MB as compared with STZ-induced diabetic rats. CTS-SeNPs and Glib diminished the level of lipid peroxidation, increased total antioxidant capacity level, as well as possessed strong inhibition against serum α-amylase and α-glucosidase activities. Diabetic animals received CTS-SeNPs, or Glib demonstrated a significant (p < 0.05) decrease in the expression level of TCF7L2 and CAPN10 genes with a significant increase in the expression level of PPAR-γ gene, compared to STZ group. The above findings clarify the promising antidiabetic and antioxidant effect of CTS-SeNPs, recommending its inclusion in the currently used protocols for the treatment of diabetes and in the prevention of its related complications. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. Methods: We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0–92.2). Results: Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). Conclusions/interpretation: Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals. [ABSTRACT FROM AUTHOR]

Diabetes mellitus "simply diabetes" is a serious case in which blood glucose levels rise because bodies of patients are unable to produce any or enough insulin, or because they are unable to use the insulin produced efficiently. It is the most prevalent type of diabetes, affecting nearly 90% of all diabetes worldwide. In patient of type 2 diabetes (T2D), his muscle, fat and liver cells can respond inappropriately to insulin, which means they can't efficiently take up glucose from blood or store it. This is known as insulin resistance. To compensate, the pancreas initially produces extra insulin. Over time, the pancreas is unable to keep up and produces insufficient insulin to maintain normal blood glucose levels. In this study, we investigate whether the two single nucleotide polymorphisms (SNPs) in the transcription factor 7-like 2 gene (TCF7L2) and KCNQ1 gene are associated with risk of developing T2D in Egyptian populations. PCR-RFLP analysis was carried out for KCNQ1 (rs2237892 and rs2237895) and TCF7L2 (rs7903146) genes for 66 T2D patients and 34 control healthy. In KCNQ1 (rs2237892) and TCF7L2 (rs7903146) for diabetic patients has a relatively high risk for diabetes, however, KCNQ1 (rs2237895) showed no statistical significant differences between the diabetic patients and the healthy group. In conclusion the TCF7L2 (rs7903146) and KCNQ1 (rs2237892) are the most unambiguous genetic factors influencing type 2 diabetes in Egypt. [ABSTRACT FROM AUTHOR]

BACKGROUND: Depending on the polymorphism of genes that that are involved in metabolism, the response of patients to different types of therapy may differ. Despite the potential effect of rs7903146 TCF7L2 and rs1042712 ADRB2 on changes in body composition in different types of therapy of early carbohydrate metabolism disorders, these associations haven’t been studied yet. AIM: To study the influence of rs7903146 TCF7L2, rs1042714 ADRB2 on changes in body fat composition in different types of therapy of early carbohydrate metabolism disorders.MATERIALS AND METHODS: The study involved patients with overweight or obesity and risk factors for Type 2 Diabetes development. All patients underwent genotyping with the real-time polymerase chain reaction, oral glucose tolerance test and bioimpedancemetry. Further, the patients were divided into two groups. First group kept a diet with the exclusion of simple and limitation of complex carbohydrates and fats. Second group took metformin in addition to the diet. Three months after bioimpedancemetry was performed again.RESULTS: The research involved 73 patients (the mean age 48±12 y.o., the mean BMI 34,27±6,18 kg/m2 ). The diet therapy group consisted of 47 people. Other 26 patients took metformin in addition to the diet. In group of diet, T allele carriers of rs7903146 TCF7L2 were characterized with more decrease in fat mass compared with CC homozygotes (- 7.90 ± 9.46% vs. -1.54 ± 8.98%, p = 0.027). CC genotype carriers of rs7903146 TCF7L2 in group of metformin and the diet had a tendency for more decrease in hip circumference compared with T allele carriers (-4.95 ± 3.34% vs. — 2.5 ± 2.96%, p = 0.064). Carriers of C allele in homozygous state of rs1042714 ADRB2, who took metformin with the diet, demonstrated more decrease in hip circumference (- 5.81 ± 3.00% vs. -2.50 ± 2.7%, p = 0.009), the tendency for decrease in fat mass (-8.28 ± 8.86% vs. — 3.20 ± 5.09%, p = 0.068) and waist circumference (-5.91 ± 4.29% vs. -3.03 ± 4.01 %, p = 0.091) compared with G allele carriers. The association of rs7903146 TCF7L2 and rs1042714 ADRB2 with changes in total body weight was not observed (p> 0.05).CONCLUSION: Single nucleotide polymorphisms rs7903146 TCF7L2 and rs1042714 ADRB2 influence on body fat composition in patients with early carbohydrate metabolism disorders in various types of treatment.

Abstract Background Type 2 diabetes mellitus (T2DM) patients show a markedly higher fracture risk and impaired fracture healing when compared to non-diabetic patients. However in contrast to type 1 diabetes mellitus, bone mineral density in T2DM is known to be normal or even regionally elevated, also known as diabetic bone disease. Charcot arthropathy is a severe and challenging complication leading to bone destruction and mutilating bone deformities. Wnt signaling is involved in increasing bone mineral density, bone homeostasis and apoptotic processes. It has been shown that type 2 diabetes mellitus is strongly associated with gene variants of the Wnt signaling pathway, specifically polymorphisms of TCF7L2 (transcription factor 7 like 2), which is an effector transcription factor of this pathway. Methods Bone samples of 19 T2DM patients and 7 T2DM patients with additional Charcot arthropathy were compared to 19 non-diabetic controls. qPCR analysis for selected members of the Wnt-signaling pathway (WNT3A, WNT5A, catenin beta, TCF7L2) and bone gamma-carboxyglutamate (BGLAP, Osteocalcin) was performed and analyzed using the 2-ΔΔCt- Method. Statistical analysis comprised one-way analysis of variance (ANOVA). Results In T2DM patients who had developed Charcot arthropathy WNT3A and WNT5A gene expression was down-regulated by 89 and 58% compared to healthy controls (p

Abstract Background Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown. Methods The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining. Results The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance. Conclusions MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.

Aim of the study was to investigate the associations of polymorphisms of some genes with overweight and some anthropometric and biochemical indicators in a population sample of the young population of Novosibirsk. Material and methods. The study was carried out on a sample of young people aged 25–35 years, residents of Novosibirsk, selected by the method of random numbers (n = 319). During the survey, a questionnaire was filled out, anthropometric measurements, blood sampling, followed by biochemical and molecular genetic studies were carried out. Results. The odds ratio (OR) to detect a carrier of the AA rs9939609 genotype of the FTO gene in the group with an increased body mass index (BMI) compared to the group with a normal BMI is 2.1 times higher (95% confidence interval (95 % CI) 1.2– 3.8; p = 0.019 in the AA vs AT+TT model). In the Kruskal – Wallis test in the general group, differences were found in carriers of different rs9939609 genotypes of the FTO gene in the thickness of the skin fold in the middle third of the right shoulder (p = 0.0008) and under the right shoulder blade (p = 0.026). In carriers of the AA genotype, these indicators were noticeably higher compared to carriers of the AT and TT genotypes. Differences in high density lipoprotein cholesterol were found in women (p = 0.032; the lowest level in the AA genotype) and low density lipoprotein cholesterol (p = 0.027; the highest value in the AA genotype). In addition, female carriers of the TT rs7903146 genotype of the TCF7L2 gene had lower diastolic blood pressure than carriers of the CT and CC genotypes (p = 0.027). The probability of detecting a male carrier of the CT or TT genotypes of the TCF7L2 gene polymorphism rs7903146 in the obese group is 0.313 (95 % CI 0.102–0.955; p = 0.036 in the CC vs CT+TT model) compared with the group with excess BMI (25 ≤ BMI < 30 kg/m2 ). The probability of detecting the allele with rs10811661 of the CDKN2AB gene in the obese group is 2.2 times higher (95 % CI 1.1–4.5; p = 0.035) compared with the group with an excess BMI. Conclusion. The association of overweight in the population sample of the young population of Novosibirsk was confirmed with rs9939609 of the FTO gene, rs7903146 of the TCF7L2 gene, rs10811661 of the CDKN2AB gene. The association of rs2237892 of the KCNQ1 gene and rs1111875 of the HHEX gene with overweight was not found. Associations of the studied SNPs with some anthropometric and biochemical indicators were found.