16 January 2025: Review Articles
COL3A1 Gene Polymorphism and Its Impact on Female Pelvic Organ Prolapse
Eighty Mardiyan Kurniawati1ACG*, Nur Anisah Rahmawati2BDE, Anis Widyasari3EFDOI: 10.12659/MSM.946367
Med Sci Monit 2025; 31:e946367
Abstract
ABSTRACT: Pelvic organ prolapse (POP) is a women’s health problem in both developed and developing countries. Various studies have found that the occurrence of POP is related to the supporting structures of the pelvic floor, including type III collagen levels. Most studies reported no correlation between collagen 3 alpha 1 (COL3A1) rs1800255 gene polymorphism and the occurrence of POP. However, the studies carried out still need to be clarified in terms of the type of research, the involvement of women of various ages, the method of diagnosing POP, and differences in the measurement of COL3A1 rs1800255 gene polymorphism. Prospectively, as the outcomes of the trials are still inconsistent, more research is required to determine which patients are at risk of pelvic organ prolapse and would benefit from preventive interventions, particularly those using collagen. This article aims to review the relationship between COL3A1 rs1800255 gene polymorphism and female pelvic organ prolapse.
Keywords: Collagen, pelvic organ prolapse, Women's Health
Introduction
One of the causes of morbidity that can reduce the quality of life in women is pelvic floor dysfunction. POP or urogenital prolapse involves the lowering of the pelvic organs causing a bulge in the vagina, uterus, or both. The prolapse that occurs can damage the anterior and posterior vaginal walls as well as the uterus or vaginal crest and manifests as a combination of the bulges above [1]. This situation is very prevalent in all countries, both developed and developing. The main cause is still unknown [2]. About 11% of women aged 80 years and older undergo pelvic reconstructive surgery, and one-third of women with pelvic organ prolapse (POP) undergo at least 1 surgical procedure [3].
Treatment for POP is expected to double in the next 30 years due to changes in population age structure and lifestyle. During their lifetime an estimated 11–12% of women will undergo surgery related to POP and incontinence, especially women aged 79 years and older, and the preoperative incidence is 29.2%. POP is the most common indication for hysterectomy in postmenopausal women [1]. Although various studies have been conducted on the mechanism of POP, the factors that cause failure to improve the treatment of prolapse are still not fully understood. Connective tissue structural abnormalities are a predisposing factor according to some scientific evidence [2]. Collagen, a key element of tissue stability (ie, quantity, ultrastructure, and organization of extracellular matrix proteins) [4], is the main component of the connective tissue of the pelvic floor. Abnormal collagen metabolism has been linked to POP and stress incontinence and is still being investigated. Continuous tissue remodeling linking collagen synthesis and degradation is essential to maintain the tensile strength of connective tissue [5].
Type III collagen is a major component of the extracellular matrix in various internal organs and skin [6]. Changes in amino acids due to genetic polymorphism are associated with Si COL3A1 genes, which can cause mechanical disorders in the supporting structures of the pelvic floor. Single-nucleotide polymorphism (SNP) is a useful tool for gene mapping in a variety of diseases [7]. The role of SNPs of the COL1A1, COL3A1, and COL18A1 genes remains controversial in pelvic organ prolapse [5]. Therefore, this article reviewed the relationship between collagen 3 alpha 1 (COL3A1) gene polymorphism rs1800255 and female pelvic organ prolapse.
Female POP: Epidemiology and Risk Factors
POP is indicated by the presence of a pelvic organ hernia within the vagina, indicating a gynecological abnormality. POP occurs due to weakness of ligaments or muscles and is categorized based on the descent of the organ. Anterior wall herniation is called cystocele. The lowering of the posterior vaginal wall is called rectocele. Lowering of the uterus, cervix, or vaginal crest is called vaginal dome prolapse [8]. POP can be detected by the presence of a protrusion in the pelvic organs that is visible to the naked eye or by concerns about urination or bowel problems [9].
The current demographic data is not sufficient to accurately estimate the true rate of pelvic organ prolapse in the population [10]. Most of the existing population-based surveys did not include physical examination data [11]. It is estimated that about 40% of women worldwide will experience POP [12], depending on whether symptoms (1–31%), pelvic examination (10–50%), or both (20–65%) are used to confirm the presence of POP. The prevalence in the general population varies greatly (1–65%) [13]. This figure increases with age. POPs, especially among women in less developed countries, remain a major health concern [12], although there is a scarcity of information about the anticipated need for POP services in developing countries [11]. Data in the United States show that about 200 000 surgeries for the treatment of POP are performed each year [13].
One technique for assessing POP is pelvic organ prolapse quantification (POP-Q), which helps in selecting an appropriate management strategy. It is not necessary to treat asymptomatic POP and mild POP can be managed with conservative methods such as pessaries and pelvic floor exercises [14]. A posterior vaginal wall or an anterior vaginal apex drop wall (cervical/uterine scar or vaginal cuff after hysterectomy) can be found when examining a prolapse, and the combination of these 2 conditions is most commonly observed [15]. The levator and pelvic floor muscles, as well as the connective tissue that supports the uterus and vagina, are responsible for the proper position of the pelvic organs [16].
While some studies have identified additional risk factors for POP, none have determined the main mechanisms that influence the occurrence of POP. Because it is not always significant when applied to diverse populations, this risk factor is debatable [17]. Vaginal delivery, parity, birth weight, age, body mass index, levator defects, and levator hiatal area are causative factors, and cesarean delivery and smoking are protective factors for primary prolapse [18]. In addition to primary prolapse, POP is a common condition with a high rate of recurrence after reconstructive surgery, and the risk factors for POP recurrence are unclear. Preoperative prolapse stage and younger age are risk factors for the recurrence of prolapse after original tissue surgery [18]. Other studies reported that parity, vaginal delivery, and BMI were risk factors for POP, and the preoperative stage was a risk factor for the recurrence of POP [19]. Other studies found that levator avulsion, preoperative stage ≥III, hiatal area on Valsalva’s maneuver, and previous pelvic floor surgery were associated with recurrence of POP [20]. Although the etiology of POP is multifactorial, there is a high correlation between pregnancy and vaginal delivery, which can lead to direct pelvic floor muscles and connective tissue injury [19].
Treatment Challenges in Pelvic Organ Prolapse
Management of pelvic organ prolapse (POP) is a common and challenging task. Although various studies have been conducted on the mechanism of POP, the factors that cause failure to improve the treatment of prolapse are still not fully understood. Connective tissue structural abnormalities are a predisposing factor according to some scientific evidence [2]. POP can be diagnosed based on the symptoms and pelvic exam, and management options include medical and surgical treatment. Medical treatment cannot correct abnormal herniations in the pelvic structure. Treatment can only help relieve symptoms [9]. POP management requires multimodal management, clinical skills, and multidisciplinary services. The integration of hormonal, non-hormonal, and surgical strategies is important and needs to be individually adapted to changing circumstances [21].
In patients with asymptomatic POP, observation is usually used. In those who do not want or are medically unfit for surgery, pessaries are an effective non-surgical option. If indicated, surgery can be performed through a transvaginal, laparoscopic/robotic, or open approach, using the patient’s own tissue or mesh augmentation [15]. Relapse is one of the disadvantages of surgical interventions. POP occurs in elderly women and requires appropriate treatment. [9]. Mesh erosion is also one of the disadvantages of surgical interventions. Newer surgical techniques for mesh placement through the abdominal or vaginal route can produce better results compared to traditional techniques [22]. In primary care, patients can be encouraged to lose weight, avoid lifting heavy objects, manage constipation, and perform pelvic floor muscle exercises [9]. In addition to surgery, there is the option of using a pessary. Although treatment with a pessary has an impressive success rate, there are some complications that patients should be informed of, such as vaginal discharge, irritation, ulceration, pain, the smell of blood, ulceration of the vaginal wall, formation of fistulas, or intestinal herniation. In addition, there is a risk of bacterial vaginosis infection [8].
Role of Collagen in the Pelvic Floor
Pelvic organ prolapse is a group of diseases caused by weakened pelvic supporting tissues, but its pathophysiology is not fully understood [23]. Collagen is one of the most important components of the extracellular matrix in connective tissue since it maintains the supporting function of the pelvic floor. Of the 28 types of collagen that have been discovered, types I to IV are the most common [24]. Collagen, a major component of mammalian skin, has been traditionally used in the manufacture of skin for thousands of years due to its diverse physicochemical properties. Collagen is the most abundant protein in mammals and is a major component of the extracellular matrix (ECM). The properties of collagen also make it an ideal building block for material engineering for a variety of biomedical applications [25].
Collagen I and III are the 2 main subtypes of pelvic tissue. Previous hypotheses have addressed the function of type I and type III collagen. Type I collagen is found in the skin, ligaments, tendons, and bones, with an estimated 80–90% of all collagen consisting of this type. Although type I and type III collagen are evenly distributed, different tissues have variable ratios of these 2 types of collagen [26]. Type III collagen is also essential for extracellular matrix function. Type III collagen is responsible for flexibility and distension, which contributes to tissue elasticity and stretching, while type I collagen is responsible for the stiffness and tensile strength of connective tissue, offering excellent mechanical strength [27].
Studies on changes in the quantity and ratio of collagen subtypes have yielded inconclusive data [28]. It is generally accepted that strong ligaments have a high ratio of type I collagen to type III collagen, while weak tissues may have a low ratio. This type III collagen polymorphism is one of the relevant risk factors for POP and can lead to poor tissue repair [7]. Collagen changes, including content, morphological and biomechanical changes, and catabolism disorders, can disrupt the supporting function of the pelvic floor and are closely related to the development of POP [23]. Research shows that POP and other collagen-related disorders may have a similar etiology involving collagen at the molecular level [29]. Collagen in the pelvic floor connective tissue of POP patients tends to be more fragile and difficult to degrade compared to non-POP patients, but it does not solve the long-standing question of the etiology of POP [28].
Abnormal metabolism and collagen deposition are associated with connective tissue disorders, such as pelvic organ prolapse [30]. In different populations, collagen tissue can have significantly different characteristics, especially in normal and prolapsed cases [31]. Another study compared healthy women and POP patients. Compared to healthy women, the collagen fibrils in the POP sample were larger, had more uneven width, and were stiffer, with aberrant D-periods. In addition, the ratio of collagen I to collagen III is twice as high in women with POP, with a concomitant reduction in total collagen count. Thus, POP is characterized by its abnormal biochemical composition and biophysical characteristics of collagen fibrils that form a loose and fragile network of fibers responsible for its poor load-bearing ability [32].
The COL3A1 rs1800255 polymorphism is a single-nucleotide polymorphism (SNP) in the alpha 1 type III collagen gene that may be associated with POP in White women [7]. Type III collagen, encoded by the COL3A1 gene, is made up of 3 identical α1(III) chains. The genetic polymorphism of the COL3A1 gene causes changes in the amino acid chain α1(III). As a result, the mechanical function of type III collagen can be affected, and the supporting structures of the pelvic floor can be impaired. The collagen 3 alpha 1 (COL3A1) gene encoding the α1 type III chain is located on chromosome 2q24.3-q31. SNP is a useful tool for mapping genes for various diseases [33]. There is a genetic variation in the COL3A1 gene that can alter gene expression and put women at risk of POP [34].
In a study examining the association of genetic polymorphism of the COL3A1 gene with POP, polymerase chain reaction (PCR) was used for most tests, while 1 study also used high-resolution melting (HRM) analysis. This method offers rapid diagnostic tests that can be used in clinical settings [35]. HRM is used to identify DNA mutations based on small changes in the DNA melting curve and has been used for genotype mutations in patients with achondroplasia and cystic fibrosis. Compared to conventional DNA sequence analysis and PCR-RFLP, HRM is a more rapid, sensitive, and relatively inexpensive method for screening gene polymorphisms in large populations. To obtain 100% specificity, the primary pair and probe used in HRM must detect all homozygous and heterozygous nucleotide substitutions. Prospectively, it contributes to the identification of patients at risk of pelvic organ prolapse and mitral valve prolapse who would benefit from preventive measures [36]. This mechanism is different from PCR, which is a laboratory technique that can amplify a specific segment of DNA into millions or billions of copies. This process is known as amplification. PCR can be used to detect diseases caused by a small number of pathogens in the body. PCR can be used to identify collagen polymorphisms by amplifying the coding sequence of collagen genes and sequencing them to identify single-nucleotide polymorphisms (SNPs) [37]. HRM analysis has analytical accuracy that depends on the fusion behavior of each particular DNA sequence. This fusion behavior is determined by many factors such as the length of the amplicons and the GC content, as well as the use of only the primary pair or in combination with the probe [38].
Collagen 3 Alpha 1 (COL3A1) Gene rs1800255 Polymorphism and Female Pelvic Organs Prolapse
In this review, we explore the association between COL3A1 RS1800255 polymorphism and its occurrence in POP. Most studies reported no correlation between COL3A1 rs1800255 polymorphism and the occurrence of POP. Our results are consistent with previous studies, which reported that findings about this relationship remain inconsistent or contradictory. A meta-analysis conducted by Niu et al gathered evidence regarding the relationship between COL3A1 and POP in White people and found that COL3A1 polymorphism rs1800255 is a risk factor for POP [7].
The studies conducted vary and are presented in Table 1. There were cohort studies, both prospective and retrospective, involving women of various ages. The comparison was also not specific to women with a POP diagnosis but included women with POP symptoms. Overall, the study by Weintraub et al (2020) involved 1032 women with pelvic organ prolapse (stage III and IV prolapse) and 1108 women without pelvic organ prolapse or grade 0 or I prolapse and had symptoms. The studies included in this review did not describe the diagnostic mechanism of POP in detail or any differences in measurements COL3A1 rs1800255 polymorphism. Standardizing diagnosis and treatment may significantly improve the ability to estimate the true incidence and prevalence of these conditions in the future [10].
Treatment of Collagen in Pelvic Floor Disorders
Experimental research related to the use of collagen is still focused on animals. Some studies have begun to discuss therapy for pelvic floor dysfunction with the use of recombinant human collagen derivative (rhCOL) prevaginally with a mouse model with FPFD. A study found that rhCOL promotes the adhesion, migration, and expression of collagen I and III of human uterosacral ligament fibroblast (hUSLF) and regulates hUSLF metabolism in vitro. rhCOL prevented adverse pelvic floor tissue renovation and improved pelvic floor function in a model of pelvic floor dysfunction in mice. In addition, rhCOL promoted ECM synthesis by activating the FAK/RhoA/ROCK signaling pathway [44]. Other studies examined the effects of human umbilical cord mesenchymal stem cells-exosomes (hucMSC-Exo) on primary vaginal fibroblast function and elucidated the underlying mechanisms involved. HucMSC-Exo normalizes the growth and function of primary fibroblasts of patients with POP by promoting cell growth and Col1 expression in vitro. HucMSC-Exo-based therapy may be ideal for treating POP safely and effectively [45].
Limitations of Current Studies
This review has several limitations. Few researchers have explored the pathological process of the rs1800255 polymorphism in COL3A1. The publications included in this review did not describe the diagnostic methods of POP and the types of pelvic organ prolapse such as cystocele, rectocele, and vaginal vault prolapse. In addition, this study did not explore the relationship of the rs1800255 polymorphism in COL3A1 with the level of POP or in patients with and without treatment, and recurrence was also not assessed. Finally, the number of samples was small and the geographic locations were limited. Experiments have increased collagen levels using stem cells, but they were limited and used experimental animals.
Future Research Directions
Future genomic association studies are needed to obtain more accurate information about how collagen affects the occurrence of POP. Future research must detail the diagnostic methods used for POP and the type of pelvic organ prolapse. Researchers need to consider collagen levels and changes in POP levels in patients with and without treatment as well as a history of recurrence. An adequate number of samples, appropriate DNA measurements, and samples from varied regions are needed to assess varying ethnicities. In addition, it is necessary to improve the quality of genotyping methodology tools (PCR-RFLP) so that research becomes faster. Future research may contribute to the identification of patients at risk of POP who would benefit from preventive measures, especially regarding the collagen approach, as the results shown in previous studies are conflicting.
Conclusions
The role of
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