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.

Keywords: ADAMTSs; Extracellular matrix synthesis and metabolism; MMPs; Pelvic organ prolapse; Single-nucleotide polymorphism; TIMPs.

Fig. 1

ADAMTS1 gene structure, indication, and the linkage disequilibrium (LD) of the SNPs. (A) Gene structure of ADAMTS1. Exons are presented in the vertical black regions. SNPs with a significant or suggestively significant association with POP are indicated by arrows in different colors: synonymous (red), missense (green), introns (blue), and 5’UTR (orange). (B) LD graphics for ADAMTS1 SNPs with r² in each of the boxes. Two SNPs showed greater correlation when the r² value was closer to 1. Boxes with no values meant r² = 1 for perfect LD