Genome-wide association studies of significant functionality of TNRC6B polymorphisms with uterine leiomyoma risk by using in silico analysis.

Background: Uterine leiomyoma (UL) is the most common benign tumor causing considerable morbidity during the reproductive years in women with contributions from environmental and genetic factors. According to the GWAS studies, there are many genes and polymorphisms that related with, somehow responsible for the UL pathogenesis, but the biological mechanisms underlying this association remain unclear.

The aim of this study: was to investigate the published GWAS studies of UL to recognize significant functionality of TNRC6B polymorphism linked with UL.

Materials and methods: Functional consequences of 5 significant SNPs were analyzed (rs739182, rs2072858, rs12484776, rs139909 and rs138039) of the TNRC6B gene involved in UL, including their epigenetic effects, expression and splicing patterns, using in silico approach and bioinformatics tools (HaploReg and GTExportal).

Results: Based on HaploReg, several epigenetic effects regulating these SNPs were found as: rs739182 (6 motifs changed, 22 enhancers, one protein bound and 5 DNAs histone markers), rs2072858(one motifs changed, 3 enhancers and one DNAs histone markers), rs12484776(3 motifs changed, 16 enhancers, 5 protein bounds and 4 DNAs histone markers), rs139909(7 motifs changed, one enhancer and one protein bound histone markers) and rs138039(one motifs changed, 9 enhancers and one DNAs histone markers). Depending on GTEx, inferred that (rs739182, rs2072858, rs12484776, rs139909 and rs138039) are associated with the expression of genes/ in tissues as: (2/5, 2/3, 4/4, 5/7,5/7), respectively. These loci except rs12484776, regulate the expression level of some genes in the UL pathophysiology important tissues (adipose subcutaneous and cell cultured fibroblasts (ADSL) of rs739182 and rs2072858, respectively, adipose subcutaneous (FAM83F) and whole blood (RP3-370M22.8) of rs139909 and whole blood (RP3-370M22.8) and cell cultured fibroblasts (MKL1) of rs138039). The GTEx dataset demonstrated that only 3 SNPs (rs2072858, rs139909 and rs138039) is associated with the alternative splicing traits (sQTL) of one gene in 1, 5 and 2 tissues, respectively. But only tissue-specific genotype-splicing associations of rs2072858 were registered in adipose subcutaneous (ADSL) involved in UL molecular pathways.

Conclusion: The in-silico analysis is a powerful approach making it possible to uncover possible metabolic pathways underlying the observed association of genetic markers with a trait.