Polymorphism of the FSHB Gene Is Associated with Endometrial Hyperplasia

The work was performed to assess the relationship of single-nucleotide polymorphisms (SNPs), which determine the concentration of sex hormones (confirmed in previously performed genome-wide studies (GWASs)), with the risk of endometrial hyperplasia (EH). The objects of the study were 1493 women, of which 520 individuals had EH; the control group consisted of 973 women. Nine SNPs that were GWAS-associated with the level of sex hormones were investigated. The correlations of SNPs that determine the level of sex hormones with EH risk were found: minor polymorphic variants rs11031002 (allele A: OR = 0.45-0.50) and rs11031005 (allele C: OR = 0.05-0.53) of the FSHB gene were associated with a low risk of developing the disease, and the TT*rs11031002-rs11031005 FSHB haplotype, at a level of statistical significance (p = 1 × 10-11) exceeding the GWAS "standard", increases the EH risk by more than 2.5 times (OR = 2.84). The 16 multilevel SNP interaction exploratory models of nine considered loci were EH-associated (padj-perm A rs11031002 and T>C rs11031005 FSHB, play a fundamental role in these models (100% and 75% of models, respectively), and two more loci, C>G rs112295236 SLC22A10 and C>A rs117585797 ANO2, are part of more than 30% of all models. Sex hormone-level genetic determinants are involved in numerous EH-significant hormone-mediated molecular pathways (regulation of gene transcription, processes of embryogenesis and development, regulation of metabolism, differentiation and maturation of the epithelium, TGFβ pathway, fat cell differentiation, etc.). In conclusion, for the first time, it was found that the genetic polymorphisms that determine an organism's sex hormone levels are associated with EH.