In silico analysis of the functional effects of BET1L rs2280543 associated with uterine leiomyoma in genome-wide studies

Title : In silico analysis of the functional effects of BET1L rs2280543 associated with uterine leiomyoma in genome-wide studies

Abstract:

The aim of this study: To identify important functional effects of BET1L rs2280543 associated with ULs based on previously published GWAS studies. Materials and Methods: The search for publications was carried out in the electronic databases PubMed in the GWAS catalog for the period from 2011 to the present about its relationship with UL. In silico approaches and bioinformatics tools (HaploReg, GTEx-portal, Gene Ontology Resource and GeneMANIA) were used to analyze its epigenetic impacts, expression and splicing patterns.
Results: The results confirmed the role of the BET1L rs2280543 in UL pathogenesis, which was found to be substantially related to the number of fibroid nodes. Allele T (ref) of SNP is associated with the lower expression of the gene in Cells - Cultured fibroblasts (β = -0.14, ð = 0.7∗10⁻⁴, pFDR ≤ 0.05) and the higher expression of the gene in Breast - Mammary Tissue (β = 0.55, ð = 4.9∗10⁻¹¹, pFDR ≤ 0.05), while alternative allele C has a risky effect for UL (OR = 1.34/1.39), and that was in two GWAS studies. Based on HaploReg, rs2280543 was discovered in the 3'-UTR. Several epigenetic effects regulating it were found as follows: 7 motifs changed, 9 enhancers and 5 DNAs histone markers. Depending on GTEx, inferred that rs2280543 is associated with the expression of 5 genes (BET1L, RP11-326C3.16, AP006621.6, PSMD13 and IFITM2) in 19 tissues, but originally reported as associated with UL, where affected the expression of 2 genes (BET1L in Adipose - Subcutaneous, Breast - Mammary Tissue and Whole Blood, and PSMD13 in Cells - Cultured fibroblasts). The GTEx dataset highlighted the regulatory function of mRNA precursor splicing patterns. According to GTEx, rs2280543 was associated with the alternative splicing traits (sQTL) of PSMD13 gene. By Gene Ontology Resource, indicated that no statistically significant biological pathways for genes associated with the studied polymorphism have been identified. The functional consequence results for these candidate SNPs suggest that this SNP may be more than surrogate, but rather has actual biological functions that contribute to UL vulnerability. It's worth noting that the protective allele T of SNP was strongly linked to increased BET1L expression in numerous human tissues. This link between UL disease risk and BET1L gene expression may suggest some underlying pathogenesis processes of UL, and more research is required in the future to elucidate this biological mechanism.
Conclusion: The in-silico analysis of GWAS  BET1L rs2280543  significant for fibroids have pronounced epigenetic effects and affect the expression of seven genes (BET1L, RP11-326C3.16, AP006621.6, PSMD13, IFITM2, DEAF1 and LINC01001), which may be the basis of their involvement in the pathophysiology of fibroids.

Biography:

Ola Alali is a 2th year PHD student in genetics from Belgorod State University, Russia. She obtained a master's degree in laboratory diagnosis in 2019 from Al-Baath University, Syria. She has published several articles at the master's stage. Likewise, a review was published in the PHD stage entitled: "The etiopathogenesis of uterine leiomyomas" and there are two articles currently under publication. Since 2011, she has been working as a member of the technical staff at Al-Baath University and several private Syrian universities, where she taught many subjects in the faculties of medicine, pharmacy and health sciences in various academic years.