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Colorectal cancer (CRC) is the third most developing cancer worldwide and Lynch syndrome (LS) accounts for 3-4% of CRC. Genetic alteration in any of DNA mismatch repair (MMR) gene is the major cause of LS that disrupt the normal upstream and downstream MMR events. Germline mutation of MLH1 in heterozygous state have an increased risk for CRC. Defective MMR pathway mostly results in microsatellite instability (MSI) that occurs in high percentage of CRC associated tumors. Here, we reported a patient with LS like metastatic CRC (mCRC) associated with other related cancers. Whole exome sequencing (WES) of the proband was performed to identify potential causative gene. Genetic screening validated by Sanger sequencing identified a heterozygous missense mutation in exon 12 of MLH1 (c.1151T>A, p.V384D). The clinical significance of identified variant was elucidated on the basis of clinicopathological data, computational predictions and various in vitro functional analysis. In silico predictions classified the variant to be deleterious and evolutionary conserved. In vitro functional studies revealed a significant decrease in protein expression because of stability defect leading to loss of MMR activity. Mutant residue found in MutL transducer domain of MLH1 that localized in the nucleus but translocation was not found to be significantly disturbed. In conclusion, our study give insight into reliability of combinatorial prediction approach of in silico and in vitro expression analysis. Hence, we highlighted the pathogenic correlation of MLH1 variant with LS associated CRC as well as help in earlier diagnosis and surveillance for improved management and genetic counselling. [ABSTRACT FROM AUTHOR]

Background: Prenatal intake of folic acid is important for prevention of NSCL/P (nonsyndromic cleft lip with or without cleft palate). Associated genes in folate pathway are major enzymes of folic acid metabolism that is crucial for preventing birth defects. The present meta-analysis aims to investigate the association between four SNPs in folate pathway genes and the risk of NSCL/P. Methods: Comprehensive bioinformatics analysis was used to predict the functional pathogenicity of genetic variation. The PubMed, Embase database and Google Scholar were searched by two researchers. Stata 11.0 software was used to analyze the results. Subgroup analysis was carried out to assess the influence of genetic background. Sensitivity analysis, regression analysis and publication analysis were also conducted to enhance the strength of our results. Results: It is estimated that the probability of two missense mutation rs1801133 in MTHFR and rs1801394 in MTRR are more likely to be damaging by bioinformatics analysis. A significant association between rs1801133 and risk of NSCL/P in two genetic models: TT genotype vs CC genotype (OR = 1.333 95%CI = 1.062-1.674, P = 0.013), and recessive model (OR = 1.325 95%CI = 1.075-1.634, P = 0.008). A significant protective association between rs1801394 GG genotype and NSCL/P in Asian (GG vs AA, OR = 0.520 95%CI = 0.321-0.841, P = 0.008) was observed. Meta-regression, sensitivity analysis, and publication bias analysis confirmed that the results of the present study were statistically significant. Conclusions: The present study identified that rs1801133 in MTHFR is associated with the risk of NSCL/P, and rs1801394 Gg genotype in MTRR play a protective role in Asian. Further, larger studies should be performed to confirm these findings. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) is involved in insulin resistance and has long been a candidate gene implicated in type 2 diabetes mellitus (T2DM), however the association between TNF-α polymorphisms -308G/A and -238G/A and T2DM remains controversial. The present study sought to verify associations between these polymorphisms and T2DM susceptibility using ameta-analysis approach. A total of 49 case-control studies were selected up to October 2018. Statistical analyses were performed by STATA 15.0 software. The odds ratios (ORs) and 95% confidence intervals were calculated to estimate associations. Meta-analyses revealed significant associations between TNF-α-308G/A and T2DM in the allele model (P=0.000); the dominant model (P=0.000); the recessive model (P=0.001); the overdominant model (P=0.008) and the codominant model (P=0.000). Subgroup analyses also showed associations in the allele model (P=0.006); the dominant model (P=0.004) and the overdominant model (P=0.005) in the Caucasian and in the allele model (P=0.007); the dominant model (P=0.014); the recessive model (P=0.000) and the codominant model (P=0.000) in the Asian. There were no associations between TNF-α-238G/A and T2DM in the overall and subgroup populations. Meta-regression, sensitivity analysis and publication bias analysis confirmed that results and data were statistically robust. Our meta-analysis suggests that TNF-α-308G/A is a risk factor for T2DM in Caucasian and Asian populations. It also indicates that TNF-α-238G/A may not be a risk factor for T2DM. More comprehensive studies will be required to confirm these associations. [ABSTRACT FROM AUTHOR]