Ksenia Kobzeva

Uterine Fibroids-Associated GWAS Loci and the Risk of Arterial Hypertension: A Pilot Study

Background: Uterine fibroids (UFs) are the most common benign tumors in women of reproductive age and are frequently associated with impaired fertility, reproductive dysfunction, and pregnancy complications. Arterial hypertension (AH) is another prevalent chronic condition in women, while increasing epidemiological evidence demonstrates the existence of a bidirectional relationship between UFs and AH. However, the genetic mechanisms underlying this association remain unclear. We hypothesized that UF-associated loci identified in genome-wide association studies (GWAS) may contribute to AH susceptibility. Methods: Genomic DNA from 606 hospitalized patients with UFs (n = 178 with comorbid AH; n = 428 AH-free) underwent allele-specific PCR amplification targeting 17 common GWAS-derived polymorphisms. Results: The rs1812266 (LOC105375949) locus was associated with a reduced risk of AH (odds ratio (OR) = 0.74; p = 0.028). Model-based multivariate dimensionality reduction (MB-MDR) analysis revealed significant gene–gene interactions (pperm ≤ 0.05) involving UF loci and AH risk, including five key variants (rs66998222, LOC102723323; rs2456181, ZNF346; rs1812266, LOC105375949; rs10929757, GREB1; rs7986407, FOXO1) appearing in multiple models. Notably, rs66998222 was observed in five models, suggesting this residue possesses a central role. For gene–environment interactions, five variants, rs66998222, LOC102723323; rs1812266, LOC105375949; rs10929757, GREB1; rs2456181, ZNF346; rs2553772, LOC105376626, appeared in multiple models, with the smoking × rs66998222 interaction being central to five models. These six risk variants subsequently underwent systematic functional annotation to characterize the potential associated biological roles. Bioinformatics analysis indicated that single nucleotide polymorphisms (SNPs) associated with oxidative stress, renin–angiotensin–aldosterone system (RAAS) function, tissue fibrosis, angiogenesis, and smooth muscle cell remodeling are common mechanisms in both UFs and AH. Cis-eQTL genes and transcription factor (TF)-linked biological processes mediate these mechanisms. Validation using the Cardiovascular Disease Knowledge Portal confirmed the relevance of several SNPs to blood pressure traits. Conclusions: To our knowledge, this is the first study to explore the genetic overlap between UFs and AH, providing novel molecular evidence for shared pathophysiological pathways. Our findings support the concept of a common genetic predisposition underlying both conditions and may inform new directions for integrated reproductive and cardiovascular health strategies.

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

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.