Matrix Metalloproteinase-9 Genetic Polymorphisms and the Risk for Advanced Pelvic Organ Prolapse

Abstract

Objective Matrix metalloproteinase-9 (MMP-9) is a protease associated with degradation of collagen and elastin. Because increased MMP-9 activity in vaginal tissue has been associated with pelvic organ prolapse, we sought to comprehensively estimate MMP-9 genetic variants and the risk for advanced prolapse. Methods This is a candidate gene association study of women with stage III-IV prolapse (cases, n=239) and women with stage 0-1 prolapse (controls, n=197). We attempted to oversample “extreme” phenotypes, including younger women with severe prolapse and older women without prolapse, in an attempt to concentrate the genetic effect. We utilized a linkage disequilibrium tagged approach to identify single nucleotide polymorphisms (SNPs) in MMP-9 to evaluate in our study. In order to minimize potential confounding by race, our analysis focused on non-Hispanic white women. We performed multivariable logistic regression to estimate the association between MMP-9 SNPs and case-control status, adjusting for age and vaginal parity. Results Women with advanced prolapse were slightly younger (64.8 ± 10.3 vs 69.0 ± 10.2 years, p=<0.001) and more likely to have had one or more vaginal deliveries (96.6% vs 82.2%, p<0.001) when compared to controls. Eight SNPs were assessed, which represented 93% coverage of the MMP-9 gene. Of these, two were associated with advanced prolapse: 1) rs3918253 (adjusted OR 0.64 [95% CI 0.41, 1.0], p=0.05) and 2) rs3918256 (adjusted OR 0.64 [95% CI 0.41, 1.01], p=0.05). Conclusions Matrix metalloproteinase-9 (MMP-9) is a biologically-plausible candidate gene for pelvic organ prolapse given our results.

Differential expression profiling of matrix metalloproteinases and tissue inhibitors of metalloproteinases in females with or without pelvic organ prolapse

“…The expression levels of MMPs were observed to be increased, but the expression levels of TIMPs were demonstrated to be reduced in prolapse patients (18). Wu et al (19) found that MMP-9 expression levels in patients with POP were significantly higher than those in a control group, indicating that MMP-9 overexpression may be involved in the occurrence of POP. Strinic et al (20) have shown that the expression levels of MMP-1 and MMP-2 in POP patients were also significantly higher that those in a control group.…”

Recent studies of genetic dysfunction in pelvic organ prolapse: The role of collagen defects

“…[57][58][59][60][61][62][63][64] Nucleotide polymorphisms in the COL3A1 genes are associated with prolapse, thus suggesting the role of defective collagen III in the genesis of prolapse. [57][58][59] Interestingly, type IV Ehlers-Danlos syndrome is due to mutations in the same COL3A1 gene.…”

“…60,61 A mutation in the gene expressing MMP is also associated with prolapse. [62][63][64] Chen et al, 62 conducted a case-control study in Taiwanese women with prolapse (n = 92) versus control (n = 152). The authors found that two genetic polymorphisms of MMP-9 were significantly associated with prolapse risk (OR: 5.41 and 5.77).…”

Circulating matrix metalloproteinases and their tissue inhibitors as markers for ethnic variation in pelvic floor tissue integrity

“…In another study, urinary collagenase assay of factors including MMP-1, -2 and -9 was the optimum pre-operative predictor of mid-urethral sling outcome in women with SUI, and revealed negative correlation with urethral closure pressure (20,21). Recent genotypic studies have identified molecular markers of dysfunction of the supportive pelvic floor connective tissue, with genetic polymorphism of MMP-1 and -9 identified in women with POP compared with controls (22,23). Studying the genetic markers of ethnic risk for pelvic floor dysfunctions including MMP polymorphism in a population of healthy and nulliparous multi-ethnic women could similarly contribute to early detection and prevention of these disorders (22,23).…”

“…Recent genotypic studies have identified molecular markers of dysfunction of the supportive pelvic floor connective tissue, with genetic polymorphism of MMP-1 and -9 identified in women with POP compared with controls (22,23). Studying the genetic markers of ethnic risk for pelvic floor dysfunctions including MMP polymorphism in a population of healthy and nulliparous multi-ethnic women could similarly contribute to early detection and prevention of these disorders (22,23). Identification of at-risk women with increased plasma MMP/TIMP ratio may be supported by further genetic evidence of polymorphism, using a simple blood test at a young age prior to first pregnancy.…”