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.