Dataset Information

The polymorphisms of extracellular matrix-remodeling genes are associated with pelvic organ prolapse.

ABSTRACT:

Introduction and hypothesis

Extracellular matrix (ECM) synthesis and metabolism abnormalities may influence the pelvic supporting system and lead to the occurrence and development of pelvic organ prolapse (POP). Genetic polymorphisms of such related genes have been increasingly studied. This study aims to explore the association between the single-nucleotide polymorphisms (SNPs) of genes encoding ECM processing enzymes (a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTSs]), ECM degrading enzymes (matrix metalloproteinases [MMPs]) and their tissue inhibitors of metalloproteinase (TIMPs), and POP.

Methods

We conducted an association study including 48 women with POP at stages III and IV and 48 women without prolapse in Chinese groups. SNPs were identified using the target region sequencing technique. We performed Fisher's exact tests to assess the association between SNPs and POP in the unadjusted model and logistic regression analysis in the adjusted model, adjusting for delivery and pregnancy.

Results

There was a significant association between TIMP2 SNP rs2277698 (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.16-0.82; P = 0.015), ADAMTS13 SNP rs149586801 (OR, 0.18; 95% CI, 0.05-0.69; P = 0.012), and ADAMTS1 SNPs rs370850 and rs422803 (OR, 3.71; 95% CI, 1.35-10.15; P = 0.011 for both), rs402007, rs428785, rs434857, and rs445784 (OR, 2.18; 95% CI, 1.05-4.56; P = 0.038 for the four), and POP in the adjusted model.

Conclusion

TIMP2, ADAMTS13, and ADAMTS1 might be candidate genes for POP. Our results provide preliminarily new evidence for future investigation of these genes in the pathophysiology of POP.

SUBMITTER: Li L

PROVIDER: S-EPMC8803794 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AIM: The molecular etiology of pelvic organ prolapse (POP) is complex and not well understood. We compared the expression/activity of extracellular matrix (ECM)-processing (procollagen I N-proteinase/ a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS]-2,-3,-14) and ECM-degrading (matrix metalloproteinase [MMP]-1, -2, -7, -8, -9, -12) enzymes and their natural tissue inhibitors (tissue inhibitors of metalloproteinase [TIMP]-1,-2,-3,-4) in vaginal tissues from premenopausal women with advanced POP (POP-Q stage ? 3) and asymptomatic controls (POP-Q = 0). STUDY DESIGN: We sampled the anterior vaginal wall of 36 premenopausal women (17 patients with POP and 19 controls) undergoing total hysterectomy. Exclusion criteria include steroid therapy, malignancy, previous pelvic surgery, and connective tissue diseases. Total RNAs and proteins were quantified by real-time polymerase chain reaction, immunoblotting, and Luminex assay; MMPs activity was analyzed by zymography and tissue localization by immunohistochemistry. RESULTS: The MMP-2 gelatinase activity as well as expression of 58-kDa isoform of ADAMTS-2 was upregulated in patients with POP, irrespective of menstrual phase status, secretory or proliferative, when compared to controls (P < .05). The TIMP-1-4 gene and TIMP-1 protein expression were significantly (P < .05) reduced, whereas protein expression of MMP-12 (pro and active forms) was significantly increased in vaginal biopsies of patients with POP in the proliferative phase of the menstrual cycle compared to corresponding controls. Analyses of MMP-12, TIMP-1, and ADAMTS-2 tissue immunostaining indicate similar localization in the vaginal specimens from control and patients with POP. CONCLUSION: Expression of ECM-remodeling proteins is altered in the vagina of premenopausal patients with severe POP. We speculate that dysregulation of MMP/TIMP complexes and ADAMTS-2 proteins may cause connective tissue defects, which result in weakened vaginal wall support and POP development.