GWAS-Significant Loci and Uterine Fibroids Risk: Analysis of Associations, Gene-Gene and Gene-Environmental Interactions.

Abstract

Background: Uterine fibroids (UF) is the most common benign tumour of the female reproductive system. We investigated the joint contribution of genome-wide association studies (GWAS)-significant loci and environment-associated risk factors to the UF risk, along with epistatic interactions between single nucleotide polymorphisms (SNPs).

Methods: DNA samples from 737 hospitalised patients with UF and 451 controls were genotyped using probe-based PCR for seven common GWAS SNPs: rs117245733 LINC00598, rs547025 SIRT3, rs2456181 ZNF346, rs7907606 STN1, SLK, rs58415480 SYNE1, rs7986407 FOXO1, and rs72709458 TERT.

Results: We observed an association between rs547025 SIRT3 and the decreased risk of UF in overall group (effect allele C, odds ratio (OR) = 0.61, 95% confidence interval (CI) = 0.43-0.866, p = 0.005). SNP rs547025 exhibits protective effects against UF exclusively in patients with normal fruit and vegetable intake (OR = 0.39, 95% CI = 0.21-0.75, p = 0.002), no history of spontaneous abortions (OR = 0.48, 95% CI = 0.33-0.70, p = 0.0001), no pelvic inflammatory diseases (PID) in anamnesis (OR = 0.55, 95% CI = 0.38-0.80, p = 0.0016), and in smokers (OR = 0.20, 95% CI = 0.06-0.65, p = 0.006). In addition, rs7907606 STN1, SLK was associated with the risk of UF in patients without a history of pelvic inflammatory diseases (PID) (OR = 1.34, 95% CI = 1.03-1.74, p = 0.028). SNPs rs547025 SIRT3 and rs7907606 STN1, SLK, displayed the strongest mono-effects (0.71% and 0.52% contribution to UF entropy) and were characterized by the most pronounced gene-gene (G×G) effects when interacting with each other (0.60% contribution to entropy). The interaction Medical abortion×rs547025 SIRT3 served as the base for all the best gene-environment (G×E) models. Medical abortions have the most pronounced mono-effect (1.15% contribution to the entropy of UF), exceeding the mono-effects of SNPs involved in the most significant G×E-models (0.01%-0.49% contribution to entropy) and spontaneous abortions (0.48% of UF entropy) and exceeding the effects of G×E interactions (0.05-0.46% of UF entropy).

Conclusions: Bioinformatics analysis showed that GWAS SNPs are involved in the molecular mechanisms of UF mainly through the regulation of vasculogenesis, cell proliferation, apoptosis, DNA damage, inflammation, hypoxia, steroid hormone metabolism, cell signaling, organ formation.