Ponomareva Liubov, Kobzeva Ksenia, Bushueva Olga
Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia.
Department of Obstetrics and Gynecology, Institute of Continuing Education, Kursk State Medical University, 305041 Kursk, Russia.
Front Biosci (Schol Ed). 2024 Dec 24;16(4):24. doi: 10.31083/j.fbs1604024.
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).
DNA samples from 737 hospitalised patients with UF and 451 controls were genotyped using probe-based PCR for seven common GWAS SNPs: rs117245733 , rs547025 rs2456181 , rs7907606 , , rs58415480 , rs7986407 , and rs72709458 .
We observed an association between rs547025 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, = 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, = 0.002), no history of spontaneous abortions (OR = 0.48, 95% CI = 0.33-0.70, = 0.0001), no pelvic inflammatory diseases (PID) in anamnesis (OR = 0.55, 95% CI = 0.38-0.80, = 0.0016), and in smokers (OR = 0.20, 95% CI = 0.06-0.65, = 0.006). In addition, rs7907606 , 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, = 0.028). SNPs rs547025 and rs7907606 , , 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 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).
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.
子宫肌瘤（UF）是女性生殖系统最常见的良性肿瘤。我们研究了全基因组关联研究（GWAS）显著位点和环境相关危险因素对UF风险的联合贡献，以及单核苷酸多态性（SNP）之间的上位性相互作用。
使用基于探针的PCR对737例住院UF患者和451例对照的DNA样本进行基因分型，检测7个常见的GWAS SNP：rs117245733、rs547025、rs2456181、rs7907606、rs58415480、rs7986407和rs72709458。
我们观察到rs547025与总体组中UF风险降低相关（效应等位基因C，优势比（OR）=0.61，95%置信区间（CI）=0.43 - 0.866，P = 0.005）。SNP rs547025仅在水果和蔬菜摄入量正常的患者中对UF具有保护作用（OR = 0.39，95% CI = 0.21 - 0.75，P = 0.002），无自然流产史的患者中（OR = 0.48，95% CI = 0.33 - 0.70，P = 0.0001），既往无盆腔炎（PID）病史的患者中（OR = 0.55，95% CI = 0.38 - 0.80，P = 0.0016），以及吸烟者中（OR = 0.20，95% CI = 0.06 - 0.65，P = 0.006）。此外，rs7907606与无盆腔炎（PID）病史患者的UF风险相关（OR = 1.34，95% CI = 1.03 - 1.74，P = 0.028）。SNP rs547025和rs7907606表现出最强的单效应（对UF熵的贡献分别为0.71%和0.52%），并且在相互作用时具有最显著的基因 - 基因（G×G）效应（对熵的贡献为0.60%）。药物流产×rs547025的相互作用是所有最佳基因 - 环境（G×E）模型的基础。药物流产具有最显著的单效应（对UF熵的贡献为1.15%），超过了参与最显著G×E模型的SNP的单效应（对熵的贡献为0.01% - 0.49%）以及自然流产的单效应（UF熵的0.48%），并且超过了G×E相互作用的效应（UF熵的0.05 - 0.46%）。
生物信息学分析表明，GWAS SNP主要通过调节血管生成、细胞增殖、凋亡、DNA损伤、炎症、缺氧、类固醇激素代谢、细胞信号传导、器官形成等参与UF的分子机制。
