Objective
Family studies and twin studies demonstrate that lower urinary tract symptoms and pelvic organ prolapse are heritable. This review aimed to identify genetic polymorphisms tested for an association with lower urinary tract symptoms or prolapse, and to assess the strength, consistency, and risk of bias among reported associations.
Study Design
PubMed and HuGE Navigator were searched up to May 1, 2014, using a combination of genetic and phenotype key words, including “nocturia,” “incontinence,” “overactive bladder,” “prolapse,” and “enuresis.” Major genetics, urology, and gynecology conference abstracts were searched from 2005 through 2013. We screened 889 abstracts, and retrieved 78 full texts. In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes. Fixed and random effects metaanalyses were conducted using codominant models of inheritance. We assessed the credibility of pooled associations using the interim Venice criteria.
Results
In pooled analysis, the rs4994 polymorphism of the ADRB3 gene was associated with overactive bladder (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7–3.6; n = 419). The rs1800012 polymorphism of the COL1A1 gene was associated with prolapse (OR, 1.3; 95% CI, 1.0–1.7; n = 838) and stress urinary incontinence (OR, 2.1; 95% CI, 1.4–3.2; n = 190). Other metaanalyses, including those for polymorphisms of COL3A1, LAMC1, MMP1, MMP3, and MMP9 did not show significant effects. Many studies were at high risk of bias from genotyping error or population stratification.
Conclusion
These metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and variation of COL1A1 with prolapse. Clinical testing for any of these polymorphisms cannot be recommended based on current evidence.
Female pelvic floor disorders , an umbrella term including urinary incontinence, bladder storage symptoms, and pelvic organ prolapse (POP) are highly prevalent. Almost one quarter of adult women report at least one clinically meaningful pelvic floor disorder, with frequent overlap between conditions. These conditions are associated with a range of comorbidities, and have a substantial impact on quality of life. There are strong associations with both age and obesity, and thus the population burden of these conditions will increase with future demographic shifts.
The existence of inherited risk factors for pelvic floor disorders has been recognized for more than 150 years, and there is clear familial aggregation for these conditions. Having an affected first-degree relative with incontinence or prolapse is associated with an approximately 2- to 3-fold increased risk of developing either condition, with effects measurable for all major subtypes of incontinence, and for anterior, apical, and posterior compartment prolapse. A relevant family history is associated with both earlier onset, and more rapidly progressive symptoms.
Family studies provide limited information on heritability, as they do not control for shared exposure to environmental risk factors. Twin studies have been used to formally quantify the heritability of lower urinary tract symptoms (LUTS) or prolapse. In a sample of 16,886 Swedish twins aged >50 years, heritability was estimated as 41% for stress incontinence surgery, and 43% for prolapse surgery. Similarly for twins aged 20-46 years from the same cohort (n = 4550), heritability was estimated as 34% for stress incontinence, 37% for urgency incontinence, and 48% for nocturia. Among a cohort of 2336 women enrolled in the Danish Twin Register, heritability ranged with age from 42-49% for urgency incontinence, 27-55% for mixed incontinence, and up to 39% for stress incontinence.
Identification of the genetic variants underlying the heritability of these conditions would provide useful markers for clinical risk, prognosis, and treatment response. In addition, however, the insights provided should help explain the pathogenesis of these complex diseases, potentially offering new drug targets and preventative strategies. The aim of this systematic review was therefore to assess which candidate polymorphisms and/or candidate genes had been tested for an association with POP or LUTS in women, and to assess the strength, consistency, and potential for bias among published associations.
Materials and Methods
Eligibility criteria
The review protocol was prospectively registered (PROSPERO 2011:CRD42012001983). We prespecified inclusion of both case-control and cross-sectional designs, with both population-based samples and other sampling methods. We included association studies testing for any genetic polymorphism at the nucleotide level, including single-nucleotide polymorphisms (SNPs), deletions, duplications, and copy-number variants, but excluded larger microscopic variants at the karyotype level.
There are no gold standard diagnostic methods for either stress urinary incontinence (SUI) or other LUTS, as these are largely subjective symptomatic diagnoses. For POP, validated staging systems, including POP Quantification, have been widely used, but again there is no universally accepted criterion for diagnosis. We therefore expected to accept diagnostic criteria for LUTS and prolapse as specified within each study. In view of heterogeneity in definitions across studies, we tested for heterogeneity between studies with different criteria in different settings. We accepted definitions based on symptom questionnaires, clinical examination, urodynamics, or other validated assessments. We considered the population of interest as women aged ≥18 years.
Search strategy
We combined searches from PubMed, HuGE Navigator, and an extensive selection of genetic, urological, and urogynecological conference reports. We searched PubMed up to May 1, 2014, without language restrictions, using a combination of genetic and phenotype key words and Medical Subject Headings (MeSH) terms: (polymorphism OR SNP OR CNV OR “copy number variation” OR mutation OR genetic OR chromosome OR VNTR OR InDel OR microsatellite) AND (nocturia OR LUTS OR incontinence OR urgency OR “overactive bladder” OR prolapse OR “Lower Urinary Tract Symptoms”[Mesh] OR “Urinary Incontinence”[MeSH] OR “enuresis”[Mesh] OR “Pelvic Organ Prolapse”[MeSH]) NOT mitral NOT carcinoma[Title] NOT cancer[Title] NOT (animals[mh] NOT humans[mh]) .
We searched HuGE Navigator, also through to May 1, 2014, using the following phenotype indexing terms: (“urination disorders” OR “urinary incontinence” OR “pelvic organ prolapse”) .
In addition we searched conference abstracts for annual meetings of the American Society of Human Genetics, American Urological Association, American Urogynecologic Society, European Association of Urology, European Society of Human Genetics, International Continence Society, International Urogynecological Association, and Society of Gynecologic Surgeons 2005 through 2013.
Screening and data extraction
We developed standardized data forms for this study, and conducted pilot screening and data extraction training exercises to achieve a high level of consensus between reviewers. All screening and data extraction was then performed independently and in duplicate by methodologically trained reviewers. Reviewers screened study reports by first screening titles and abstracts to select papers for full-text assessment, then screening full-text papers to confirm eligibility of the articles. Screening discrepancies were resolved by adjudication. We hand searched reference lists of all included articles, applying the same standardized screening process. When >1 report was identified for the same association in the same study population, we included the publication with the largest sample size.
We contacted study authors by email, with a reminder after 1 month, for clarifications, additional information about methodology, and additional subgroup analyses where necessary. Data extracted included information on the setting for each study, details of the sampling strategy and sampled populations (age, parity, ethnic/racial composition, and body mass index), the overall sample size and proportion genotyped, the outcome assessments used and phenotypic definitions, the genotyping method employed, and the genotyping quality control applied. Where possible we extracted or requested from authors full genotype frequencies among both cases and controls.
Statistical analysis and risk of bias assessments
For polymorphisms assessed in ≥2 studies for the same phenotype assessed with similar case definitions, we conducted fixed or random effects metaanalyses as appropriate using the Metan package (Stata 12.1; StataCorp, College Station, TX). In all cases, we worked from genotype or allele frequencies, rather than using precalculated effect sizes. We did not pool data from studies with mixed male and female samples, unless results stratified by sex were available. We did not pool data from studies with composite case definitions (ie, any urinary incontinence) with those with simple case definitions (ie, SUI). In the absence of a clear rationale supporting any specific model of inheritance, we used the allelic association test/codominant models of inheritance for all polymorphisms. We assessed the credibility of pooled associations using the interim Venice criteria ( Appendix ; Supplementary Figure ). We used the I 2 statistic as a measure of between study heterogeneity. We recalculated the power of each study, and retested for departure from Hardy-Weinberg equilibrium. We made assessments of risk of bias in phenotype definitions, genotyping, and population stratification. We used the Harbord test of funnel plot asymmetry, and the significance chasing bias test to investigate possible reporting biases. Reporting of this review complies with recommendations both of the HuGE Handbook, and the PRISMA statement.
Results
Search outcomes
We screened 889 abstracts, and retrieved 78 full texts ( Figure 1 ). In all, 27 published studies and 7 unpublished studies provided data ( Table 1 ) regarding polymorphisms in or near 32 different genes ( Supplementary Table 1 ). Most research interest has focused on variation in genes implicated in extracellular matrix organization and disassembly, with particular focus on collagen and metalloendopeptidase genes ( Supplementary Table 2 ). A number of studies also addressed a variety of steroid hormone receptor genes. All studies investigated POP, SUI, or overactive bladder, with no available data on other individual LUTS.
| Study | Journal and year | Country | Descent, ethnicity, race a | Gene symbols(s) | Polymorphism(s) dbSNP ID | Case definition | Control definition | Cases genotyped, n | Controls genotyped, n |
|---|---|---|---|---|---|---|---|---|---|
| Allen-Brady et al | Obstet Gynecol 2011 | United States, The Netherlands | White and Northern European descent | LINC0108 b ZFAT Intergenic Intergenic Intergenic COL18A1 | rs1455311 rs1036819 rs430794 rs8027714 rs1810636 rs2236479 | Surgically treated/recurrent POP with family history | Population controls | 191 | 3036 |
| Campeau et al | Neurourol Urodyn 2011 (ICS abstract) | United States | Not stated | MMP1 | rs1144393 rs498186 rs473509 | Surgically treated POP | Hospital controls “without POP” | 63 | 93 |
| Chen et al | Am J Obstet Gynecol 2010 | United States | African American and Caucasian | LAMC1 | rs10911193 rs20563 rs20558 | POP stage >II | POP stage <II | 165 | 246 |
| Chen et al | Int Urogynecol J 2008 | Taiwan | Taiwanese | ESR1 | rs17847075 rs2207647 rs2234693 rs3798577 rs2228480 | POPQ ≥2 | POPQ <2 | 88 | 153 |
| Chen et al | Acta Obstet Gynecol 2009 | Taiwan | Taiwanese | PGR | rs500760 rs484389 | POPQ ≥2 | POPQ <2 | 87 | 150 |
| Chen et al | Am Soc Hum Genet 2013 | United States | African American and Hispanic American | PRCP b | rs2086297 | Symptomatic SUI | No SUI | ≈3343 | ≈8183 |
| Chen et al | Int Urogynecol J 2008 | Taiwan | Taiwanese | COL3A1 | rs1800255 rs1801184 | POPQ ≥2 | POPQ <2 | 84 | 147 |
| Chen et al | Eur J Obstet Gynecol 2010 | Taiwan | Taiwanese | MMP9 | rs3918242 rs17576 rs2250889 | POPQ ≥2 | POPQ <2 | 92 | 152 |
| Chen et al | Eur J Obstet Gynecol 2008 | Taiwan | Taiwanese | ESR2 | rs2987983 rs1271572 rs944459 rs1256049 rs1255998 | POPQ ≥2 | POPQ <2 | 69 | 141 |
| Cho et al | Yonsei Med J 2009 | Korea | Korean | COL1A1 | rs1800012 | Surgically treated POPQ ≥3 | POPQ = 0 | 15 | 15 |
| Choy et al | ICS abstract 2007 | Hong Kong | Chinese | EDN1 | rs5370 rs10478694 | POPQ ≥2 | Hospital “normal’’ controls and HapMap Han Chinese controls | 60 (rs5370) and 67 (rs10478694) | 210 |
| Cornu et al | World J Urol 2011 | France | Caucasian | ESR1 CYP17A1 CYP19A1 AR | rs2234693 rs743572 rs60271534 CAG repeat | Treated for UI (30 UUI, 107 SUI) | No UI or OAB | 121 | 66 |
| Feiner et al | Int Urogynecol J 2009 | Israel | Caucasian or Ashkenazi-Jewish | COL1a1 | rs1800012 | POPQ ≥3 | POPQ <2 | 36 | 36 |
| Ferrari et al | Arch Gynecol Obstet 2012 | Italy | Italian | COL1a1 MMP9 MMP1 MMP3 | rs1800012 rs3918242 rs1799750 rs3025058 | POPQ ≥2 | POPQ <2 | 137 | 96 |
| Ferreira et al | Am J Obstet Gynecol 2011 | Brazil | White or nonwhite | ADRB3 | rs4994 | Symptomatic OAB without severe SUI | No LUTS | 49 | 169 |
| Ferrell et al | Reprod Sci 2009 | United States | African American or Caucasian | LOXL1 | rs16958477 | POP stage ≥II | POP stage <II | 137 | 130 |
| Fu et al | J Urol 2009 (AUA abstract) | United States | Not stated | LAMC1 LOXL1 | rs10911193 | POP stage ≥III | No POP or UI | 61 | 33 |
| Honda et al | Neurourol Urodyn 2014 | Japan | Japanese | ADRb3 | rs4994 | Symptomatic OAB | No OAB | 100 | 101 |
| Jeon et al | J Urol 2009 | Korea | Korean | COL3a1 | rs111929073 | POPQ ≥2 | POPQ <2 and no SUI | 36 | 36 |
| Kim et al | Eur J Obstet Gynecol Reprod Biol 2014 | Korea | Korean | GSTM1 GSTT1 GSTP1 | Null Null rs1695 | POPQ ≥3 | POPQ <2 | 189 | 156 |
| Kim et al | Menopause 2014 | Korea | Korean | PARP1 | rs1136410 | POPQ ≥3 | POPQ <2 | 185 | 155 |
| Lince et al | Int Urogynecol J 2014 | The Netherlands | ≈99% Dutch | COL3a1 | rs1800255 | POPQ ≥2 | POPQ <2 | 272 | 82 |
| Martins et al | Neurourol Urodyn 2011 | Brazil | White or nonwhite | COL3a1 | rs111929073 | POP stage ≥III | POP stage <II | 107 | 209 |
| Noronha et al | J Investig Med 2010 | Brazil | Predominant European/white | HTR2A | rs6313 | Symptomatic UI | Self-reported continent women, and population controls | 68 | 849 |
| Ozbek et al | J Obstet Gynaecol Res 2013 | Turkey | Caucasian | LOXL1 | rs2165241 rs3825942 rs1048661 | Symptomatic SUI | No UI | 93 | 75 |
| Rodrigues et al | Int Urogynecol J 2008 | Brazil | White or nonwhite | COL1a1 | rs1800012 | POP stage ≥III | POP stage <II and no SUI | 107 | 209 |
| Romero and Jamison | J Pelv Med Surg 2008 | United States | White | MMP1 MMP2 MMP3 MMP8 MMP9 MMP10 MMP11 TIMP1 TIMP3 | rs2071230 rs7201 rs679620 rs35866072 rs17576 rs17435959 rs738789 rs4898 rs2016293 | POPQ ≥3 | POPQ <2 and no UI | 45 | 38 |
| Sioutis et al | Int Urogynecol J 2011 | Greece | Greek | COL1a1 | rs1800012 | SUI confirmed with urodynamics and positive pad test, and postmenopausal | Healthy postmenopausal | 45 | 45 |
| Skorupski | Int Urogynecol J 2009 (IUGA abstract) | Poland | Polish | COL1a1 | rs1800012 | POPQ ≥2 | POPQ <2 and no UI | 120 | 97 |
| Skorupski et al | Am J Obstet Gynecol 2006 | Poland | Polish | COL1a1 | rs1800012 | SUI confirmed with urodynamics and positive pad test | POPQ <2 and no UI | 50 | 50 |
| Skorupski et al | Ginekol Polska 2010 | Poland | Polish | MMP1 MMP3 | rs1799750 rs3025058 | POPQ ≥2 | POPQ <2 | 132 | 133 |
| Takeda et al | ICS Abstract 2002 | Japan | Japanese | ADRb3 ADRA1A | rs4994 rs1048101 | Any LUTS (includes mixed group of women and men) | No LUTS | 27 | 17 |
| Velez Edwards et al | Am Soc Hum Gen 2013 | United States | African American and Hispanic American | CPE b Intergenic | rs28573326 rs113518633 | POP stage ≥I | POP stage = 0 | 1427 | 1274 |
| Vishwajit et al | ICS abstract 2009 | United States | Not stated | MMP1 | rs1799750 | SUI with varying POP | Neither SUI nor POP | 40 | 15 |
| Wu et al | Am J Obstet Gynecol 2012 | United States | Non-Hispanic white | LAMC1 | rs10911193 rs1413390 rs20558 rs20563 rs10911206 rs2296291 rs12041030 rs12739316 rs3768617 rs2483675 rs10911211 rs41475048 rs1058177 rs12073936 | POPQ ≥3 | POPQ <2 | 239 | 197 |
| Wu et al | Obstet Gynecol 2012 | United States | Non-Hispanic white | MMP9 | rs3918253 rs3918256 rs3918278 rs17576 rs2274755 rs17577 rs2236416 rs3787268 | POPQ ≥3 | POPQ <2 | 239 | 197 |
a Assessments of descent/ethnicity/race as specified in primary publications, or from additional data from authors, or assumed for countries with low ethnic heterogeneity including Taiwan, Korea, and Japan
b Genome-wide significant genes ( P <5 × 10 -8 ) reported in genome-wide association study.
Quantitative syntheses were possible for 11 polymorphisms in or near 7 genes: beta 3 adrenoceptor ( ADRB3 ); collagen, type I, alpha 1 ( COL1A1 ); collagen, type 3, alpha 1 ( COL3A1 ); laminin gamma 1 ( LAMC1 ); matrix metalloproteinase-1 ( MMP1 ); matrix metalloproteinase-3 ( MMP3 ); and matrix metalloproteinase-9 ( MMP9 ).
ADRB3
Variation in the beta-3 adrenoceptor, particularly of the rs4994 SNP, also known as Trp64Arg, has been extensively investigated in association with obesity, type 2 diabetes mellitus, and other metabolic syndrome phenotypes. The beta-3 adrenoceptor is highly expressed in bladder, and mediates detrusor muscle relaxation. A beta-3 adrenoceptor agonist has recently been approved for treatment of overactive bladder symptoms. One conference abstract, and 2 published papers provided relevant information on the common rs4994 missense mutation, of which 2 could be included in metaanalysis. In the initial report, in a heterogeneous Japanese sample of 13 men and 31 women, with diverse urological pathologies including neurogenic bladder and benign prostatic hyperplasia, the rs4994 SNP was not associated with LUTS (odds ratio [OR], 1.20; 95% confidence interval [CI], 0.32–4.47). Results were not available stratified by sex, and could not be included in quantitative synthesis. Subsequent reports used larger samples of Japanese women, and Brazilian women ( Table 1 ), and looked specifically at the overactive bladder phenotype, finding a large effect size (pooled OR, 2.46; 95% CI, 1.67–3.60) ( Figure 2 ), with no heterogeneity. Despite a lack of information about genotyping quality control (QC), and some risk of population stratification, this large effect size confers some protection from bias, providing Venice grading BBB, or moderate epidemiological credibility ( Table 2 ).
| Gene | SNP | Phenotype | Studies, n | Sample with minor allele a | Pooled OR | I 2 % | Deviation from HWE b | Proteus effect | Harbord test P value | Funnel plot | Genotyping QC | Risk of population stratification | Venice rating | Overall credibility |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ADRB3 | rs4994 | OAB | 2 | 136 | 2.46 | 0.0 | None | None | n/a | n/a | Not reported | Yes c | BBB | Moderate |
| COL1A1 | rs1800012 | SUI | 2 | 92 | 2.09 | 0.0 | Yes | None | n/a | n/a | Not reported | Low | CBC | Weak |
| POP | 4 | 249 | 1.33 | 0.0 | None | None | .88 | Symmetric | Not reported | Yes c | BBB | Moderate | ||
| COL3A1 | rs1800255 | POP | 2 | 257 | 1.19 | 0.0 | None | Yes | n/a | n/a | Not reported /appropriate | None | BCB | Weak |
| rs111929073 | POP | 2 | 115 | 0.56 | 83.7 | None | None | n/a | n/a | Not reported | Yes c | BCB | Weak | |
| LAMC1 | rs10911193 | POP | 4 | 218 | 1.12 | 0.0 | None | None | .97 | Symmetric | Appropriate /not reported | Low | BCB | Weak |
| rs20563 | POP | 3 | 525 | 1.12 | 0.0 | None | None | .86 | Symmetric | Appropriate | Low | BCA | Weak | |
| rs20558 | POP | 3 | 551 | 1.12 | 0.0 | None | None | .93 | Symmetric | Appropriate | Low | BCA | Weak | |
| MMP1 | rs1799750 | POP | 2 | 234 | 0.83 | 74.9 | Yes | Yes | n/a | n/a | Not reported | Low | BCC | Weak |
| SUI | 2 | 150 | 0.88 | 3.4 | None | None | n/a | n/a | Not reported | Yes c | BCC | Weak | ||
| MMP3 | rs3025058 | POP | 2 | 381 | 1.11 | 0.0 | Yes | None | n/a | n/a | Not reported | Low | BCC | Weak |
| MMP9 | rs3918242 | POP | 2 | 99 | 1.25 | 0.0 | None | None | n/a | n/a | Not reported | Low | CCC | Weak |
| rs17576 | POP | 3 | 473 | 1.05 | 68.9 | None | None | .72 | Symmetric | Not reported /appropriate | Low | BCB | Weak |
a Pooled sample size of participants with minor allele
b Checked in controls and whole population, and metaanalysis rechecked excluding studies with significant departure
c Studies each include populations with mixed descent groups without reported adjustment.
COL1A1
rs1800012 also known as the Sp1-binding site polymorphism of collagen, type I, alpha 1, modifies transcription factor binding and gene expression. It has been most extensively studied in association with osteoporosis, where the minor allele is modestly associated with reduced bone mineral density and increased fracture risk. Collagen, type I, alpha 1 is a major structural component of the vaginal epithelium and endopelvic fascia. The available data on gene and protein expression in pelvic tissue from women with prolapse or stress incontinence are heterogeneous but suggest increased COL1A1 expression with reduced type 1 collagen content. Seven studies provided data on the rs1800012 SNP in association with either POP or stress incontinence, of which 6 could be included in quantitative syntheses.
Five studies reported associations of rs1800012 with anatomical POP in Brazilian, Israeli, Polish, Italian, and Korean populations ( Table 1 ). The Korean study found only the wild type GG allele among all 30 participants, and could not be included in quantitative synthesis. Despite each individual study being underpowered, the pooled effect size for the remaining 4 studies was significant (OR, 1.33; 95% CI, 1.02–1.73) ( Figure 3 ) with low inconsistency. With limited information about genotyping QC, and a possible risk of population stratification in 2 samples, we considered that bias could not be fully excluded, providing Venice grading BBB, or moderate epidemiological credibility ( Table 2 ).
Two studies of Polish and Greek women reported associations of the same polymorphism with stress incontinence, in both cases using a combined symptomatic and objectively measured case definition. The pooled effect size was large (OR, 2.09; 95% CI, 1.35–3.22) ( Figure 3 ) with no heterogeneity (I 2 = 0%). There was significant deviation from Hardy-Weinberg equilibrium in one sample, suggesting significant potential for bias. However, exclusion of this study would not change the result. With high risk of bias the Venice grading was CBC, or weak epidemiological credibility ( Table 2 ).
COL3A1
A large number of mutations in collagen, type 3, alpha 1 have been associated with vascular Ehlers-Danlos syndrome. Inconsistent evidence suggests that urinary incontinence and prolapse may be prevalent among women with Ehlers-Danlos. Collagen, type 3 has a particular function in tissue repair, and is typically overexpressed in pelvic tissues from women with prolapse. We identified studies testing associations with 2 missense variants rs1800255 and rs111929073, as well as 1 synonymous SNP rs1801184. Both missense variants had been tested in 2 studies, and therefore could be combined in quantitative syntheses. Separate Taiwanese and Dutch studies found a nonsignificant pooled association between rs1800255 and anatomic prolapse (OR, 1.19; 95% CI, 0.88–1.61) ( Figure 4 ), with no heterogeneity ( Table 2 ).
For rs111929073, separate Korean and Brazilian samples demonstrated a nonsignificant pooled effect (OR, 0.56; 95% CI, 0.19–1.61) ( Figure 4 ) with high heterogeneity (I 2 = 83.7%, P < .01). Case definitions were similar for the 2 studies, making this an unlikely source of heterogeneity. The primary Korean study had suggested a large protective effect of the minor allele, and the heterogeneity between studies might instead be explained by differences in populations, or a simple Proteus effect.
LAMC1
Laminin gamma 1 is 1 of 3 kinds of laminin chain that combine to make different laminin isoforms. These extracellular matrix glycoproteins are an important constituent of basement membranes, with roles in cell adhesion and migration. LAMC1 was initially proposed as a candidate gene for prolapse in a linkage study of 9 individuals from a family affected by early-onset severe prolapse. We identified 3 further studies all from the United States that attempted to replicate this initial report of an association with rs10911193, with all 3 including testing of additional SNPs ( Table 1 ).
All 3 individual studies found no association for rs10911193, with a nonsignificant pooled effect (OR, 1.13; 95% CI, 0.83–1.53) ( Figure 5 ) and no heterogeneity. There was no evidence of small study bias or publication bias. Genotyping QC was generally well documented for these studies, and population stratification appropriately accounted for. Two of the studies provided further data on rs20563 and rs20558, 2 missense SNPs in near perfect linkage disequilibrium, but again with nonsignificant pooled effects (both OR, 1.12; 95% CI, 0.92–1.38) ( Figure 5 ) and no heterogeneity.
MMP1
Matrix metalloproteinase-1, also known as interstitial collagenase, is one of a number of enzymes that cleave collagen type 1. The MMP1 gene is up-regulated in pelvic tissues of women with prolapse. Common variants of this gene have been extensively studied in association with chronic obstructive pulmonary disease, cardiovascular disease, and a number of cancers including of lung, colon, and breast. We identified 2 unpublished studies from the United States, and 2 published studies of Polish and Italian samples assessing associations between MMP1 variants and stress incontinence or prolapse. Of these, 2 studies reported on rs1799750 in association with prolapse, with a nonsignificant pooled effect (OR, 0.97; 95% CI, 0.76–1.25) ( Figure 6 ) with no heterogeneity. One of the 2 studies included demonstrated marked deviation from Hardy-Weinberg equilibrium, and exclusion of this study would however leave a single eligible study with a nonsignificant association (OR, 0.88; 95% CI, 0.60–1.27). For the 2 studies testing associations with SUI, the pooled effect was again nonsignificant (OR, 0.87; 95% CI, 0.63–1.20), with no heterogeneity.
MMP3
Matrix metalloproteinase-3, also known as stromelysin-1, is an enzyme that degrades a number of extracellular matrix components including collagen type 3 and elastin. Similarly to MMP1 , its common variants have received most research attention in association with cardiovascular disease, and a number of cancers. We identified 2 studies again of women of European descent, both testing associations of rs3025058, known as the 5A/6A promoter InDel, with prolapse. The pooled effect was again nonsignificant (OR, 1.11; 95% CI, 0.86–1.43) ( Figure 7 ) with no heterogeneity.
MMP9
Matrix metalloproteinase-9, also known as 92-kDa type IV collagenase, degrades collagen type 4 and type 5. Some evidence suggests increased activation of MMP9 in pelvic tissues from women with prolapse. Like MMP1 and MMP3 , its common polymorphisms have been linked to chronic obstructive pulmonary disease, cardiovascular disease, and some cancers. We identified 4 studies of Italian, Taiwanese, and white US samples, assessing 10 different polymorphisms in association with prolapse. Three studies contributed to a metaanalysis of the rs17576 missense polymorphism. The pooled effect was nonsignificant (OR, 1.02; 95% CI, 0.81–1.28) ( Figure 8 ) but with significant heterogeneity (I 2 = 68.9%, P = .04). Case definitions were similar for the 3 studies, making this an unlikely source of heterogeneity. All studies demonstrated Hardy-Weinberg equilibrium, and we judged a low risk of population stratification. The single study among Asian women suggested a narrowly significant effect (OR, 0.62; 95% CI, 0.40–0.98), while subgroup analysis of the 2 white US samples showed no pooled effect (OR, 1.22; 95% CI, 0.93–1.60). Two studies contributed to metaanalysis of rs3918242, with a nonsignificant effect (OR, 1.25; 95% CI, 0.83–1.89) ( Figure 8 ) and no heterogeneity.
