Genome-wide association studies (GWAS) have identified an association between polymorphisms in the FTO gene and obesity. The FTO: rs9939609, an intronic variant, is considered a risk allele for developing diabesity in homozygous and heterozygous forms. This study aimed to investigate the molecular structure of the available inhibitors specific to the FTO mutations along with the rs9939609 variant. We identified the best-suited inhibitor molecules for each mutant type containing the rs9939609 risk allele. Missense mutations unique to obesity and containing the risk allele of rs9939609 were retrieved from dbSNP for this study. Further stability testing for the mutations were carried out using DynaMut and iStable tools. Three mutations (G187A, M223V, and I492V) were highly destabilizing the FTO structure. These three mutants and native FTO were docked with each of the nine-inhibitor molecules collected from literature studies with the help of PyRx and AutoDock.Further structural behavior of the mutants and native FTO were identified with molecular dynamics simulations and MM-PBSA analyses, along with the 19complex inhibitor compound. We found the compound 19complex exhibited better binding interactions and is the top candidate inhibitor for the M223V and I492V mutants. This study provided insights into the structural changes caused due to mutations in FTO, and the binding mechanism of the inhibitor molecules. It could aid in developing antiobesity drugs for treating patients with mutations and risk alleles predisposing to obesity.
Gastrointestinal (GI) cancers are known to have a high incidence worldwide and require an early diagnosis to successfully treat them, providing higher survival rates and better quality of life for the patients. MicroRNA-27a is a well-known oncogene that plays a significant role in various GI cancers. It is known to upregulate the expression of numerous oncogenes leading to cancer progression. The miR-27a harbors two polymorphisms rs895819 and rs11671784 which alter the disease susceptibility by interfering with the maturation and expression of miR-27a.In the current study, we aimed to investigate the role played by these polymorphisms in cancers of the GI tract. We conducted a case-control study with 210 GI cancer cases and 210 cancer-free controls to analyze the effect of these polymorphisms. The rs895819 polymorphism was genotyped using PCR-RFLP, and rs11671784 was genotyped on a MassARRAY platform. The association analysis failed to bring out any significant association of the polymorphisms with GI cancer risk. However, genotype-phenotype interaction analysis revealed that the rs895819 was found to increase the risk GI cancers along with the presence of risk factors such as socioeconomic status, diabetes mellitus, hypertension, alcohol consumption, and tobacco chewing.
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