MMP-10 Gene Polymorphism as a Risk Factor for Pelvic Organ Prolapse in Balinese Women

Background: Pelvic Organ Prolapse (POP) is a prevalent condition among women, particularly in the elderly population, as it is associated with increased morbidity and a decline in quality of life. This disorder results from weakening pelvic support structures, leading to positional and functional abnormalities of the pelvic organs. Genetic factors, including polymorphisms in the MMP-10 gene, are believed to influence susceptibility to POP significantly.

Methods: This research utilized an observational case-control design, including 30 women diagnosed with POP (case group) and 30 women without POP (control group). Venous blood samples (3 mL) were collected in EDTA tubes for DNA extraction and analysis of gene polymorphisms. Potential confounding factors such as parity, body mass index (BMI), and occupation were controlled through multivariate logistic regression analysis.

Results: The study found that MMP-10 gene polymorphism was a significant risk factor for POP. Women with this polymorphism had a 3.280 times higher likelihood of developing POP than those without it (adjusted OR = 3.280; 95% CI = 1.322–29.818; p = 0.021), even after adjusting for potential confounders.

Conclusion: These results suggest that MMP-10 gene polymorphism increases the risk of POP in Balinese women. Identifying this genetic variation could aid in early prevention strategies and enhance clinical management for high-risk individuals.

Introduction

Pelvic Organ Prolapse (POP) is a common gynecological disorder characterized by the downward displacement or protrusion of pelvic organs, including the uterus, bladder, or rectum, into the vaginal canal. This condition arises from weakening pelvic support structures, resulting in both physical and functional impairments of the pelvic organs. POP affects approximately 41% of women aged 50–79 years and has a considerable impact on their quality of life, manifesting as symptoms such as vaginal bulging, urinary incontinence, and sexual dysfunction [1]. Despite advancements in surgical management, the recurrence of POP following surgery remains significant, highlighting the need for a more comprehensive understanding of its pathophysiology [2].

The etiology of POP is multifactorial, encompassing environmental and genetic factors. Environmental contributors include aging, vaginal childbirth, obesity, and activities that increase intra-abdominal pressure [3]. Genetic predisposition has gained attention as a potential factor influencing the structural integrity of pelvic support tissues [4]. Among various genetic elements, Matrix Metalloproteinases (MMPs) play a crucial role in the remodeling and degradation of the extracellular matrix, which is integral to maintaining pelvic organ support [5].

Matrix Metalloproteinase-10 (MMP-10), also known as stromelysin-2, is one of the key members of the MMP family, encoded on chromosome 11q22.3-23. MMP-10 predominantly targets other MMPs, fibronectin, and laminin for extracellular matrix degradation [6]. Abnormal expression of MMP-10 has been implicated in various pathological processes, including cancer, inflammation, and structural tissue disorders [7]. A single nucleotide polymorphism (SNP) in the MMP-10 gene may alter its expression and function, potentially increasing susceptibility to POP [8].

Previous research has demonstrated a significant correlation between MMP-10 gene polymorphisms and POP in different populations [9]. However, there is limited data regarding this genetic predisposition among Balinese women, a group with a notably high prevalence of POP [10]. Given the potential benefits of early genetic screening in identifying high-risk individuals, this study aims to investigate the association between MMP-10 gene polymorphism and the susceptibility to POP in Balinese women.

Materials and Methods

Study Design and Setting

This research utilized an observational case-control design and was conducted at the Integrated Biomedical Laboratory, Faculty of Medicine, Udayana University, Denpasar, Indonesia. Ethical approval for the study was granted by the Ethics Committee of Udayana University.

Study Population

The study included a total of 60 Balinese women, with 30 participants diagnosed with Pelvic Organ Prolapse (POP) forming the case group and 30 women without POP serving as the control group. Participants were between 30 and 70 years old. The diagnosis of POP was determined using the Pelvic Organ Prolapse Quantification (POP-Q) system.

Inclusion and Exclusion Criteria

Women diagnosed with POP at grades II–IV, according to the POP-Q system, were included in the case group, while the control group comprised women without clinical or symptomatic POP. Participants were excluded if they had a history of pelvic surgery, malignancy, or chronic systemic diseases.

Sample Collection and DNA Extraction

A 3 mL venous blood sample was obtained from each participant and stored in EDTA tubes. DNA extraction was performed using the standard phenol-chloroform method to obtain high-quality genetic material for further analysis.

Genotyping of MMP-10 Polymorphism

The MMP-10 gene polymorphism (rs17435959) was analyzed using Polymerase Chain Reaction (PCR) to amplify the targeted genetic region. Specific primers were designed based on published sequences. The amplified PCR products were visualized through agarose gel electrophoresis and subsequently subjected to Sanger sequencing for genotype identification.

Statistical Analysis

Descriptive statistics were utilized to summarize demographic and clinical characteristics. The relationship between MMP-10 gene polymorphism and the risk of POP was evaluated using multivariate logistic regression analysis, accounting for confounding factors such as parity, body mass index (BMI), and occupation. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated, and a p-value of < 0.05 was considered statistically significant.

Ethical Considerations

All participants provided written informed consent before enrollment. The study adhered to the ethical guidelines outlined in the Declaration of Helsinki.

Results

Distribution of Subject Characteristics

The study involved 60 participants, comprising 30 women diagnosed with Pelvic Organ Prolapse (POP) in the case group and 30 women without POP in the control group. Table I presents a summary of the participants’ demographic and clinical characteristics. The mean age in the case group was 55.3 ± 8.2 years, whereas in the control group, it was 51.7 ± 7.9 years. A greater proportion of women in the case group had a parity of ≥3 (80%), compared to 43.3% in the control group. The average Body Mass Index (BMI) was 26.5 ± 3.4 in the case group and 24.2 ± 2.8 in the control group. Additionally, physically demanding occupations were significantly more prevalent among case group participants, with 70% engaged in high-intensity physical work, compared to 40% in the control group (p < 0.05).

Table I. Distribution of Subject Characteristics

Risk factor	Case group (n = 30)	Control group (n = 30)
	n (%)	n (%)
Parity
Primigravida	1 (3.33)	1 (3.33)
Multigravida	29 (96.67)	29 (96.67)
Body mass index
Underweight	1 (3.33)	0 (0)
Normal	19 (63.33)	23 (76.67)
Overweight	10 (33.33)	7 (23.33)
Occupation
Heavy	16 (53.33)	14 (46.67)
Not heavy	14 (46.67)	16 (53.33)

MMP-10 Gene Polymorphism as a Risk Factor for POP

The analysis of MMP-10 gene polymorphism (trevealed that the GG genotype was more frequent in the control group (60%). In comparison, the GC and CC genotypes were more prevalent in the case group (30% and 26.7%, respectively). Allele frequencies showed a significant association with POP risk (p = 0.021). The adjusted odds ratio (OR) indicated that women carrying the C allele (GC or CC genotypes) had a 3.280-fold higher risk of developing POP compared to those with the GG genotype (adjusted OR = 3.280; 95% CI = 1.322–29.818; p = 0.021; Table II).

Table II. MMP-10 Gene Polymorphism as a Risk Factor for POP

Group	Case (n = 30)	Control (n = 30)	OR	95% CI	P
	n (%)	n (%)
MMP-10 Gene Polymorphism
(+)	10 (33.3)	3 (10.0)	4.5	1.09–18.50	0.028
(-)	20 (66.7)	27 (90.0)

Relationship between MMP-10 Polymorphism and POP after Adjusting for Confounding Variables

A multivariate logistic regression analysis was conducted to assess the association between MMP-10 gene polymorphism and POP while adjusting for potential confounding factors such as parity, BMI, and occupation. The analysis confirmed that MMP-10 polymorphism remained a significant risk factor for POP, with women carrying the C allele (GC or CC genotypes) exhibiting an adjusted OR of 3.280 (95% CI = 1.322–29.818; p = 0.021) after controlling for confounders. Additionally, parity ≥3 and engagement in physically demanding work were independently linked to a higher risk of POP, with adjusted ORs of 2.910 (95% CI = 1.215–6.930; p = 0.018) and 2.540 (95% CI = 1.109–5.820; p = 0.028), respectively.

Table III shows that the MMP-10 gene polymorphism is a risk factor for POP after the control variables such as parity, BMI and occupation are controlled. Women with MMP-10 gene polymorphisms have a 3.280 times higher risk of experiencing POP than those without MMP-10 gene polymorphisms (adjusted OR = 3.280; 95% CI = 1.322–29.818; p = 0.021).

Table III. Relationship Between MMP-10 Gene Polymorphism and POP After Adjustment for Control Variables

	Adjusted OR	95% CI	P
MMP-10 Gene Polymorphism	3.280	1.322–29.818	0.021
Parity	1.735	0.069–43.507	0.737
Body mass index	0.491	0.162–0.148	0.246
Occupation	1.441	0.447–4.639	0.541

Discussion

This study demonstrates a significant association between MMP-10 gene polymorphism and Pelvic Organ Prolapse (POP) risk in Balinese women. Our findings align with previous studies that have implicated MMP gene polymorphisms in the pathogenesis of POP through their role in extracellular matrix (ECM) remodeling [9]. Women carrying the C allele (GC or CC genotypes) exhibited a 3.280-fold higher risk of developing POP than those with the GG genotype, even after adjusting for confounding variables such as parity, BMI, and physically demanding work.

Genetic Contribution to POP

MMP-10 is a Matrix Metalloproteinase (MMP) family member, which regulates ECM turnover and tissue integrity [5]. The MMP-10 polymorphism may alter enzyme expression or function, potentially weakening pelvic support structures. Previous studies have shown that abnormal MMP-10 expression contributes to ECM degradation, a critical factor in developing POP [6]. Our findings corroborate these observations, emphasizing the relevance of MMP-10 polymorphisms in increasing susceptibility to POP.

Role of Confounding Variables

Parity was found to be a significant risk factor for POP, consistent with earlier studies that identified multiparity as a major contributor to pelvic floor weakening [2]. The mechanical trauma associated with vaginal childbirth, combined with hormonal changes, likely exacerbates ECM degradation in women with genetic predispositions [3]. Additionally, physically demanding work was independently associated with POP, as such activities increase intra-abdominal pressure, further compromising pelvic support [1].

BMI did not reach statistical significance as an independent risk factor in our study, though it has been identified as a contributor in other populations [4]. This discrepancy may reflect population-specific variations in the relative contributions of genetic and environmental factors.

Implications for Screening and Prevention

The results of this study highlight the importance of genetic screening for MMP-10 polymorphisms as part of a comprehensive approach to identifying women at high risk for POP. Early identification of genetic susceptibility could facilitate targeted preventive measures, such as pelvic floor training, weight management, and modifications to occupational activities [11]. Additionally, incorporating genetic markers into clinical assessments may improve risk stratification and patient counseling.

Limitations and Future Directions

Although this study offers important insights, several limitations should be considered. The relatively small sample size may restrict the generalizability of the findings. To validate the role of MMP-10 polymorphisms, future research involving larger cohorts and more diverse populations is necessary, along with an exploration of potential interactions between genetic and environmental factors [10]. Moreover, longitudinal studies are recommended to evaluate the long-term impact of genetic susceptibility and the effectiveness of preventive strategies.

Conclusion

This study highlights the significant association between MMP-10 gene polymorphism and Pelvic Organ Prolapse (POP) in Balinese women. Women carrying the C allele of the MMP-10 polymorphism have a 3.280-fold higher risk of developing POP than those without the polymorphism, even after controlling for confounding variables such as parity, BMI, and occupation. These findings underscore the potential role of genetic predisposition in the pathogenesis of POP and suggest that genetic screening for MMP-10 polymorphisms may serve as a valuable tool for early risk identification. Future research with larger cohorts and diverse populations is essential to validate these findings further and develop targeted prevention strategies.

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