Identifying the Effects of Pathogenic Genetic Variations in Human HOXA10, ESR1, and FSHB in Endometriosis and Fibroids.

Abstract

Endometriosis and fibroids stand as the leading health problems related to reproduction in women. In that sense, the present study was conducted to unravel genetic factors and single nucleotide polymorphisms (SNPs) in the genes of ESR1, FSHB, and HOXA10, which have been identified to play vital roles in these diseases. We have examined the missense variants for their effects on the respective proteins using six in silico tools: SIFT, PolyPhen-2, Provean, Panther, SNP&Go, and Predict SNP. The studies for effects on protein stability were done by MutPred2, I-Mutant, MuPro, and structural modeling. The evolutionary conservation was calculated by Consurf and PTMs were analyzed. Protein-protein interactions were investigated using STRING, and gene-gene interaction was studied using GeneMANIA. In view of these deep analyses, the ESR1 SNP rs121913044 (V364E, T > A) was selected for further in vitro validation. It is through the association testing using ARMS PCR of the rs121913044 SNP with endometriosis and fibroid blood samples from Rawalpindi and Islamabad that obtained a highly significant association with the former disease with p = <0.0001 and significant of association with the latter, fibroids, with a p-value of 0.0191. Therefore, this integrated approach gives significance to computational and experimental methods in better understanding reproductive diseases.