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Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women

Open AccessPublished:August 08, 2014DOI:https://doi.org/10.1016/j.ajog.2014.08.005

      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 In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes.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.

      Key words

      Female pelvic floor disorders, an umbrella term including urinary incontinence, bladder storage symptoms, and pelvic organ prolapse (POP) are highly prevalent.
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      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,
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      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.
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      A systematic review of clinical studies on hereditary factors in pelvic organ prolapse.
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      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.
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      Genetic influence on stress urinary incontinence and pelvic organ prolapse.
      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.
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      • Lundholm C.
      • et al.
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      Among a cohort of 2336 women enrolled in the Danish Twin Register,
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      • Christensen K.
      Genetic and environmental influences on urinary incontinence: a Danish population-based twin study of middle-aged and elderly women.
      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).

      Cartwright R, Mangera A, Kirby A, et al. PROSPERO: a systematic review of candidate gene association studies of lower urinary tract symptoms and pelvic organ prolapse in women. Available at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42012001983. Accessed Oct. 4, 2013.

      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
      • Harris R.J.
      • Bradburn M.J.
      • Deeks J.J.
      • et al.
      Metan: fixed- and random-effects meta-analysis.
      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
      • Ioannidis J.P.
      • Boffetta P.
      • Little J.
      • et al.
      Assessment of cumulative evidence on genetic associations: interim guidelines.
      (Appendix; Supplementary Figure). We used the I2 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
      • Ioannidis J.P.A.
      • Trikalinos T.A.
      An exploratory test for an excess of significant findings.
      to investigate possible reporting biases. Reporting of this review complies with recommendations both of the HuGE Handbook, and the PRISMA statement.

      Little J, Higgins J, Bray M, Ioannidis J, Khoury M. The HuGENet HuGE review handbook, version 1.0, 2006. Available at: http://www.med.uottawa.ca/public-health-genomics/web/assets/documents/huge_review_handbook_v1_0.pdf. Accessed Sept. 11, 2014.

      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred Reporting Items for Systematic Reviews and Meta-Analyses: 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.
      Figure thumbnail gr1
      Figure 1Flowchart outlining literature search and article evaluation process
      a 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 abstracts 2005 through 2014, using online search interfaces and/or full text search of abstract book PDFs; b Includes studies enrolling only men (n = 122), enrolling only children (n = 2), narrative reviews or letters (n = 12), inapplicable phenotype (n = 2), and other study designs including pharmacogenetic studies, gene expression studies, or methylation studies (n = 8); c Authors contacted by email for additional data from 18 studies.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      Table 1Included studies
      StudyJournal and yearCountryDescent, ethnicity, race
      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
      Gene symbols(s)Polymorphism(s) dbSNP IDCase definitionControl definitionCases genotyped, nControls genotyped, n
      Allen-Brady et al
      • Allen-Brady K.
      • Cannon-Albright L.
      • Farnham J.M.
      • et al.
      Identification of six loci associated with pelvic organ prolapse using genome-wide association analysis.
      Obstet Gynecol 2011United States, The NetherlandsWhite and Northern European descentLINC0108b

      ZFAT

      Intergenic

      Intergenic

      Intergenic

      COL18A1
      rs1455311

      rs1036819

      rs430794

      rs8027714

      rs1810636

      rs2236479
      Surgically treated/recurrent POP with family historyPopulation controls1913036
      Campeau et al

      Campeau L, Gorbachinsky I, Stancill J, Rohazinski J, Andersson KE. Characterization of SNPs within the MMP-1 promotor region in women with and without POP. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 31, 2011; Glasgow, United Kingdom.

      Neurourol Urodyn 2011 (ICS abstract)United StatesNot statedMMP1rs1144393

      rs498186

      rs473509
      Surgically treated POPHospital controls “without POP”6393
      Chen et al
      • Chen C.
      • Hill L.D.
      • Schubert C.M.
      • Strauss J.F.
      • Matthews C.A.
      Is laminin gamma-1 a candidate gene for advanced pelvic organ prolapse?.
      Am J Obstet Gynecol 2010United StatesAfrican American and CaucasianLAMC1rs10911193

      rs20563

      rs20558
      POP stage >IIPOP stage <II165246
      Chen et al
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Estrogen receptor alpha polymorphism is associated with pelvic organ prolapse risk.
      Int Urogynecol J 2008TaiwanTaiwaneseESR1rs17847075

      rs2207647

      rs2234693

      rs3798577

      rs2228480
      POPQ ≥2POPQ <288153
      Chen et al
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Progesterone receptor polymorphism is associated with pelvic organ prolapse risk.
      Acta Obstet Gynecol 2009TaiwanTaiwanesePGRrs500760

      rs484389
      POPQ ≥2POPQ <287150
      Chen et al

      Chen C, Rajkovic A, Park A, Heiss G, Hendrix S, Franceschini N. Uncovering loci associated with urinary incontinence in African and Hispanic American women. Presented as a poster at: the American Society of Human Genetics Annual Meeting; Oct. 25, 2013; Boston, MA.

      Am Soc Hum Genet 2013United StatesAfrican American and Hispanic AmericanPRCP brs2086297Symptomatic SUINo SUI≈3343≈8183
      Chen et al
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Estrogen receptor alpha polymorphism is associated with pelvic organ prolapse risk.
      Int Urogynecol J 2008TaiwanTaiwaneseCOL3A1rs1800255

      rs1801184
      POPQ ≥2POPQ <284147
      Chen et al
      • Chen H.Y.
      • Lin W.Y.
      • Chen Y.H.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Matrix metalloproteinase-9 polymorphism and risk of pelvic organ prolapse in Taiwanese women.
      Eur J Obstet Gynecol 2010TaiwanTaiwaneseMMP9rs3918242

      rs17576

      rs2250889
      POPQ ≥2POPQ <292152
      Chen et al
      • Chen H.Y.
      • Wan L.
      • Chung Y.W.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Estrogen receptor beta gene haplotype is associated with pelvic organ prolapse.
      Eur J Obstet Gynecol 2008TaiwanTaiwaneseESR2rs2987983

      rs1271572

      rs944459

      rs1256049

      rs1255998
      POPQ ≥2POPQ <269141
      Cho et al
      • Cho H.J.
      • Jung H.J.
      • Kim S.K.
      • Choi J.R.
      • Cho N.H.
      • Bai S.W.
      Polymorphism of a COLIA1 gene Sp1 binding site in Korean women with pelvic organ prolapse.
      Yonsei Med J 2009KoreaKoreanCOL1A1rs1800012Surgically treated POPQ ≥3POPQ = 01515
      Choy et al

      Choy KW, Wong ASW, Cheon WC, et al. Genetic association study in women with pelvic organ prolapse. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 24, 2007; Rotterdam, The Netherlands.

      ICS abstract 2007Hong KongChineseEDN1rs5370

      rs10478694
      POPQ ≥2Hospital “normal’’ controls and HapMap Han Chinese controls60 (rs5370) and 67 (rs10478694)210
      Cornu et al
      • Cornu J.N.
      • Merlet B.
      • Cussenot O.
      • et al.
      Genetic susceptibility to urinary incontinence: implication of polymorphisms of androgen and estrogen pathways.
      World J Urol 2011FranceCaucasianESR1

      CYP17A1

      CYP19A1

      AR
      rs2234693

      rs743572

      rs60271534

      CAG repeat
      Treated for UI (30 UUI, 107 SUI)No UI or OAB12166
      Feiner et al
      • Feiner B.
      • Fares F.
      • Azam N.
      • Auslender R.
      • David M.
      • Abramov Y.
      Does COLIA1 SP1-binding site polymorphism predispose women to pelvic organ prolapse?.
      Int Urogynecol J 2009IsraelCaucasian or Ashkenazi-JewishCOL1a1rs1800012POPQ ≥3POPQ <23636
      Ferrari et al
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      Arch Gynecol Obstet 2012ItalyItalianCOL1a1

      MMP9

      MMP1

      MMP3
      rs1800012

      rs3918242

      rs1799750

      rs3025058
      POPQ ≥2POPQ <213796
      Ferreira et al
      • Ferreira C.E.
      • Fonseca A.M.
      • Silva I.D.
      • Girao M.J.
      • Sartori M.G.
      • Castro R.A.
      The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder.
      Am J Obstet Gynecol 2011BrazilWhite or nonwhiteADRB3rs4994Symptomatic OAB without severe SUINo LUTS49169
      Ferrell et al
      • Ferrell G.
      • Lu M.
      • Stoddard P.
      • et al.
      A single nucleotide polymorphism in the promoter of the LOXL1 gene and its relationship to pelvic organ prolapse and preterm premature rupture of membranes.
      Reprod Sci 2009United StatesAfrican American or CaucasianLOXL1rs16958477POP stage ≥IIPOP stage <II137130
      Fu et al
      • Fu R.
      • Hagstrom S.
      • Daneshgari F.
      Mutation screen of lysyl oxidase-like-1 and laminin gamma 1 variant in patients with advanced pelvic organ prolapse.
      J Urol 2009 (AUA abstract)United StatesNot statedLAMC1

      LOXL1
      rs10911193POP stage ≥IIINo POP or UI6133
      Honda et al
      • Honda K.
      • Yamaguchi O.
      • Nomiya M.
      • et al.
      Association between polymorphism of beta3-adrenoceptor gene and overactive bladder.
      Neurourol Urodyn 2014JapanJapaneseADRb3rs4994Symptomatic OABNo OAB100101
      Jeon et al
      • Jeon M.J.
      • Chung S.M.
      • Choi J.R.
      • Jung H.J.
      • Kim S.K.
      • Bai S.W.
      The relationship between COL3A1 exon 31 polymorphism and pelvic organ prolapse.
      J Urol 2009KoreaKoreanCOL3a1rs111929073POPQ ≥2POPQ <2 and no SUI3636
      Kim et al
      • Kim J.Y.
      • Kim E.J.
      • Jeon M.J.
      • Kim R.
      • Lee M.W.
      • Kim S.W.
      Association between susceptibility to advanced pelvic organ prolapse and glutathione S-transferase P1 Ile105Val polymorphism.
      Eur J Obstet Gynecol Reprod Biol 2014KoreaKoreanGSTM1

      GSTT1

      GSTP1
      Null

      Null

      rs1695
      POPQ ≥3POPQ <2189156
      Kim et al
      • Kim J.Y.
      • Kim E.J.
      • Jeon M.J.
      • Kim H.
      • Moon Y.J.
      • Bai S.W.
      Association between the poly(ADP-ribose) polymerase-1 gene polymorphism and advanced pelvic organ prolapse.
      Menopause 2014KoreaKoreanPARP1rs1136410POPQ ≥3POPQ <2185155
      Lince et al
      • Lince S.L.
      • van Kempen L.C.
      • Dijkstra J.R.
      • IntHout J.
      • Vierhout M.E.
      • Kluivers K.B.
      Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G>A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population.
      Int Urogynecol J 2014The Netherlands≈99% DutchCOL3a1rs1800255POPQ ≥2POPQ <227282
      Martins et al
      • Martins K de F.
      • de Jármy-DiBella Z.I.K.
      • da Fonseca A.M.R.M.
      • et al.
      Evaluation of demographic, clinical characteristics, and genetic polymorphism as risk factors for pelvic organ prolapse in Brazilian women.
      Neurourol Urodyn 2011BrazilWhite or nonwhiteCOL3a1rs111929073POP stage ≥IIIPOP stage <II107209
      Noronha et al
      • Noronha J.A.
      • Schwanke C.H.
      • Machado D.C.
      • et al.
      Association between T102C polymorphism of serotonin 2A receptor gene and urinary incontinence in older women.
      J Investig Med 2010BrazilPredominant European/whiteHTR2Ars6313Symptomatic UISelf-reported continent women, and population controls68849
      Ozbek et al
      • Ozbek E.
      • Polat E.C.
      • Ozcan L.
      • Otunctemur A.
      • Emrence Z.
      • Ustek D.
      TT polymorphism in rs2165241 and rs1048661 region in lysyl oxidase like-1 gene may have a role in stress urinary incontinence physiopathology.
      J Obstet Gynaecol Res 2013TurkeyCaucasianLOXL1rs2165241

      rs3825942

      rs1048661
      Symptomatic SUINo UI9375
      Rodrigues et al
      • Rodrigues A.M.
      • Girão M.J.B.C.
      • da Silva I.D.C.G.
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      COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse.
      Int Urogynecol J 2008BrazilWhite or nonwhiteCOL1a1rs1800012POP stage ≥IIIPOP stage <II and no SUI107209
      Romero and Jamison
      • Romero A.
      • Jamison M.
      Are single nucleotide polymorphisms associated with pelvic organ prolapse?.
      J Pelv Med Surg 2008United StatesWhiteMMP1

      MMP2

      MMP3

      MMP8

      MMP9

      MMP10

      MMP11

      TIMP1

      TIMP3
      rs2071230

      rs7201

      rs679620

      rs35866072

      rs17576

      rs17435959

      rs738789

      rs4898

      rs2016293
      POPQ ≥3POPQ <2 and no UI4538
      Sioutis et al
      • Sioutis D.
      • Economou E.
      • Lambrinoudaki I.
      • Tsamadias V.
      • Creatsa M.
      • Liapis A.
      Sp1 collagen I A1 polymorphism in women with stress urinary incontinence.
      Int Urogynecol J 2011GreeceGreekCOL1a1rs1800012SUI confirmed with urodynamics and positive pad test, and postmenopausalHealthy postmenopausal4545
      Skorupski
      • Skorupski P.
      Does polymorphism of the gene encoding alpha-1 chain of collagen type 1 influence the risk of pelvic organ prolapse?.
      Int Urogynecol J 2009 (IUGA abstract)PolandPolishCOL1a1rs1800012POPQ ≥2POPQ <2 and no UI12097
      Skorupski et al
      • Skorupski P.
      • Król J.
      • Starega J.
      • Adamiak A.
      • Jankiewicz K.
      • Rechberger T.
      An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence.
      Am J Obstet Gynecol 2006PolandPolishCOL1a1rs1800012SUI confirmed with urodynamics and positive pad testPOPQ <2 and no UI5050
      Skorupski et al
      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      Ginekol Polska 2010PolandPolishMMP1

      MMP3
      rs1799750

      rs3025058
      POPQ ≥2POPQ <2132133
      Takeda et al

      Takeda M, Araki I, Kamiyama M, Takihana Y, Tanabe N. Single nucleotide polymorphism of alpha1a and beta3-adrenoceptors in urological patients with and without micturition symptoms–possible mechanism for hyperactivity of adrenergic nerve and tailor-made medicine. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 30, 2002; Heidelberg, Germany.

      ICS Abstract 2002JapanJapaneseADRb3

      ADRA1A
      rs4994

      rs1048101
      Any LUTS (includes mixed group of women and men)No LUTS2717
      Velez Edwards et al

      Velez Edwards DR, Ward RM, Giri A, et al. Trans-ethnic GWAS of pelvic organ prolapse among African American and Hispanic postmenopausal women of the Women's Health Initiative. Presented as a poster at: the American Society of Human Genetics Annual Meeting; Oct. 25, 2013; Boston, MA.

      Am Soc Hum Gen 2013United StatesAfrican American and Hispanic AmericanCPE
      Genome-wide significant genes (P <5 × 10-8) reported in genome-wide association study.


      Intergenic
      rs28573326

      rs113518633
      POP stage ≥IPOP stage = 014271274
      Vishwajit et al

      Vishwajit S, Rohozinski J, Badlani G, Andersson K-E. Association of MMP1 promoter variant with stress urinary incontinence and pelvic organ prolapse in women. Presented as a poster at: the International Continence Society Annual Meeting; Oct. 3, 2009; San Francisco, CA.

      ICS abstract 2009United StatesNot statedMMP1rs1799750SUI with varying POPNeither SUI nor POP4015
      Wu et al
      • Wu J.M.
      • Visco A.G.
      • Grass E.A.
      • et al.
      Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.
      Am J Obstet Gynecol 2012United StatesNon-Hispanic whiteLAMC1rs10911193

      rs1413390

      rs20558

      rs20563

      rs10911206

      rs2296291

      rs12041030

      rs12739316

      rs3768617

      rs2483675

      rs10911211

      rs41475048

      rs1058177

      rs12073936
      POPQ ≥3POPQ <2239197
      Wu et al
      • Wu J.M.J.
      • Visco A.G.A.
      • Grass E.A.E.
      • et al.
      Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse.
      Obstet Gynecol 2012United StatesNon-Hispanic whiteMMP9rs3918253

      rs3918256

      rs3918278

      rs17576

      rs2274755

      rs17577

      rs2236416

      rs3787268
      POPQ ≥3POPQ <2239197
      AUA, American Urological Association; ICS, International Continence Society; IUGA, International Urogynecological Association; LUTS, lower urinary tract symptoms; OAB, overactive bladder; POP, pelvic organ prolapse; POPQ, Pelvic Organ Prolapse Quantification system; SNP, single-nucleotide polymorphism; SUI, stress urinary incontinence; UI, urinary incontinence; UUI, urge urinary incontinence.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      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.
      • Aizawa N.
      • Homma Y.
      • Igawa Y.
      Effects of mirabegron, a novel β3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin.
      A beta-3 adrenoceptor agonist has recently been approved for treatment of overactive bladder symptoms.
      • Khullar V.
      • Amarenco G.
      • Angulo J.C.
      • et al.
      Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomized European-Australian phase 3 trial.
      • Chapple C.R.
      • Kaplan S.A.
      • Mitcheson D.
      • et al.
      Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder.
      One conference abstract,

      Takeda M, Araki I, Kamiyama M, Takihana Y, Tanabe N. Single nucleotide polymorphism of alpha1a and beta3-adrenoceptors in urological patients with and without micturition symptoms–possible mechanism for hyperactivity of adrenergic nerve and tailor-made medicine. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 30, 2002; Heidelberg, Germany.

      and 2 published papers
      • Honda K.
      • Yamaguchi O.
      • Nomiya M.
      • et al.
      Association between polymorphism of beta3-adrenoceptor gene and overactive bladder.
      • Ferreira C.E.
      • Fonseca A.M.
      • Silva I.D.
      • Girao M.J.
      • Sartori M.G.
      • Castro R.A.
      The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder.
      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).

      Takeda M, Araki I, Kamiyama M, Takihana Y, Tanabe N. Single nucleotide polymorphism of alpha1a and beta3-adrenoceptors in urological patients with and without micturition symptoms–possible mechanism for hyperactivity of adrenergic nerve and tailor-made medicine. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 30, 2002; Heidelberg, Germany.

      Results were not available stratified by sex, and could not be included in quantitative synthesis. Subsequent reports used larger samples of Japanese women,
      • Honda K.
      • Yamaguchi O.
      • Nomiya M.
      • et al.
      Association between polymorphism of beta3-adrenoceptor gene and overactive bladder.
      and Brazilian women
      • Ferreira C.E.
      • Fonseca A.M.
      • Silva I.D.
      • Girao M.J.
      • Sartori M.G.
      • Castro R.A.
      The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder.
      (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).
      Figure thumbnail gr2
      Figure 2Forest plot of rs4994 SNP of ADRB3 and overactive bladder
      Forest plot of studies
      • Honda K.
      • Yamaguchi O.
      • Nomiya M.
      • et al.
      Association between polymorphism of beta3-adrenoceptor gene and overactive bladder.
      • Ferreira C.E.
      • Fonseca A.M.
      • Silva I.D.
      • Girao M.J.
      • Sartori M.G.
      • Castro R.A.
      The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder.
      reporting associations between rs4994 single-nucleotide polymorphism (SNP)* of beta 3 adrenoceptor gene and overactive bladder. *RefSNP alleles C/T. Plot presented as risk associated with minor allele C.
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      Table 2Interim Venice assessments of epidemiological credibility for each metaanalysis
      GeneSNPPhenotypeStudies, nSample with minor allele
      Pooled sample size of participants with minor allele
      Pooled ORI2 %Deviation from HWE
      Checked in controls and whole population, and metaanalysis rechecked excluding studies with significant departure
      Proteus effectHarbord test P valueFunnel plotGenotyping QCRisk of population stratificationVenice ratingOverall credibility
      ADRB3rs4994OAB21362.460.0NoneNonen/an/aNot reportedYes
      • Ferreira C.E.
      • Fonseca A.M.
      • Silva I.D.
      • Girao M.J.
      • Sartori M.G.
      • Castro R.A.
      The relationship between the Trp 64 Arg polymorphism of the beta 3-adrenoceptor gene and idiopathic overactive bladder.
      Studies each include populations with mixed descent groups without reported adjustment.
      BBBModerate
      COL1A1rs1800012SUI2922.090.0Yes
      • Skorupski P.
      • Król J.
      • Starega J.
      • Adamiak A.
      • Jankiewicz K.
      • Rechberger T.
      An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence.
      Nonen/an/aNot reportedLowCBCWeak
      POP42491.330.0NoneNone.88SymmetricNot reportedYes
      • Rodrigues A.M.
      • Girão M.J.B.C.
      • da Silva I.D.C.G.
      • Sartori M.G.F.
      • Martins K de F.
      • Castro R de A.
      COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse.
      • Feiner B.
      • Fares F.
      • Azam N.
      • Auslender R.
      • David M.
      • Abramov Y.
      Does COLIA1 SP1-binding site polymorphism predispose women to pelvic organ prolapse?.
      Studies each include populations with mixed descent groups without reported adjustment.
      BBBModerate
      COL3A1rs1800255POP22571.190.0NoneYesn/an/aNot reported
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Wang J.C.
      • Tsai F.J.
      • Tsai C.H.
      Collagen type 3 alpha 1 polymorphism and risk of pelvic organ prolapse.
      /appropriate
      • Lince S.L.
      • van Kempen L.C.
      • Dijkstra J.R.
      • IntHout J.
      • Vierhout M.E.
      • Kluivers K.B.
      Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G>A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population.
      NoneBCBWeak
      rs111929073POP21150.5683.7NoneNonen/an/aNot reportedYes
      • Martins K de F.
      • de Jármy-DiBella Z.I.K.
      • da Fonseca A.M.R.M.
      • et al.
      Evaluation of demographic, clinical characteristics, and genetic polymorphism as risk factors for pelvic organ prolapse in Brazilian women.
      Studies each include populations with mixed descent groups without reported adjustment.
      BCBWeak
      LAMC1rs10911193POP42181.120.0NoneNone.97SymmetricAppropriate
      • Wu J.M.
      • Visco A.G.
      • Grass E.A.
      • et al.
      Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.
      • Chen C.
      • Hill L.D.
      • Schubert C.M.
      • Strauss J.F.
      • Matthews C.A.
      Is laminin gamma-1 a candidate gene for advanced pelvic organ prolapse?.
      /not reported
      • Fu R.
      • Hagstrom S.
      • Daneshgari F.
      Mutation screen of lysyl oxidase-like-1 and laminin gamma 1 variant in patients with advanced pelvic organ prolapse.
      LowBCBWeak
      rs20563POP35251.120.0NoneNone.86SymmetricAppropriateLowBCAWeak
      rs20558POP35511.120.0NoneNone.93SymmetricAppropriateLowBCAWeak
      MMP1rs1799750POP22340.8374.9Yes
      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      Yesn/an/aNot reportedLowBCCWeak
      SUI21500.883.4NoneNonen/an/aNot reportedYes

      Vishwajit S, Rohozinski J, Badlani G, Andersson K-E. Association of MMP1 promoter variant with stress urinary incontinence and pelvic organ prolapse in women. Presented as a poster at: the International Continence Society Annual Meeting; Oct. 3, 2009; San Francisco, CA.

      Studies each include populations with mixed descent groups without reported adjustment.
      BCCWeak
      MMP3rs3025058POP23811.110.0Yes
      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      Nonen/an/aNot reportedLowBCCWeak
      MMP9rs3918242POP2991.250.0NoneNonen/an/aNot reportedLowCCCWeak
      rs17576POP34731.0568.9NoneNone.72SymmetricNot reported
      • Chen L.
      • Wang T.
      • Liu L.
      • Shen Y.
      • Wan C.
      • Wen F.
      Matrix metalloproteinase-9 -1562C/T promoter polymorphism confers risk for COPD: a meta-analysis.
      /appropriate
      • Wu J.M.
      • Visco A.G.
      • Grass E.A.
      • et al.
      Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.
      LowBCBWeak
      Three-letter code corresponds to A through C ratings of amount of evidence, its consistency, and its protection from bias (Supplementary Figure).
      HWE, Hardy Weinberg Equilibrium; OAB, overactive bladder; OR, odds ratio; POP, pelvic organ prolapse; QC, quality control; SNP, single-nucleotide polymorphism; SUI, stress urinary incontinence.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      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.
      • Jin H.
      • Evangelou E.
      • Ioannidis J.P.A.
      • Ralston S.H.
      Polymorphisms in the 5′ flank of COL1A1 gene and osteoporosis: meta-analysis of published studies.
      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.
      • Chen B.
      • Yeh J.
      Alterations in connective tissue metabolism in stress incontinence and prolapse.
      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,
      • Rodrigues A.M.
      • Girão M.J.B.C.
      • da Silva I.D.C.G.
      • Sartori M.G.F.
      • Martins K de F.
      • Castro R de A.
      COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse.
      Israeli,
      • Feiner B.
      • Fares F.
      • Azam N.
      • Auslender R.
      • David M.
      • Abramov Y.
      Does COLIA1 SP1-binding site polymorphism predispose women to pelvic organ prolapse?.
      Polish,
      • Skorupski P.
      Does polymorphism of the gene encoding alpha-1 chain of collagen type 1 influence the risk of pelvic organ prolapse?.
      Italian,
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      and Korean
      • Cho H.J.
      • Jung H.J.
      • Kim S.K.
      • Choi J.R.
      • Cho N.H.
      • Bai S.W.
      Polymorphism of a COLIA1 gene Sp1 binding site in Korean women with pelvic organ prolapse.
      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,
      • Rodrigues A.M.
      • Girão M.J.B.C.
      • da Silva I.D.C.G.
      • Sartori M.G.F.
      • Martins K de F.
      • Castro R de A.
      COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse.
      • Feiner B.
      • Fares F.
      • Azam N.
      • Auslender R.
      • David M.
      • Abramov Y.
      Does COLIA1 SP1-binding site polymorphism predispose women to pelvic organ prolapse?.
      we considered that bias could not be fully excluded, providing Venice grading BBB, or moderate epidemiological credibility (Table 2).
      Figure thumbnail gr3
      Figure 3Forest plot of studies of rs1800013 SNP of COL1A1
      Forest plot of studies
      • Rodrigues A.M.
      • Girão M.J.B.C.
      • da Silva I.D.C.G.
      • Sartori M.G.F.
      • Martins K de F.
      • Castro R de A.
      COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse.
      • Feiner B.
      • Fares F.
      • Azam N.
      • Auslender R.
      • David M.
      • Abramov Y.
      Does COLIA1 SP1-binding site polymorphism predispose women to pelvic organ prolapse?.
      • Skorupski P.
      Does polymorphism of the gene encoding alpha-1 chain of collagen type 1 influence the risk of pelvic organ prolapse?.
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      • Skorupski P.
      • Król J.
      • Starega J.
      • Adamiak A.
      • Jankiewicz K.
      • Rechberger T.
      An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence.
      • Sioutis D.
      • Economou E.
      • Lambrinoudaki I.
      • Tsamadias V.
      • Creatsa M.
      • Liapis A.
      Sp1 collagen I A1 polymorphism in women with stress urinary incontinence.
      reporting associations between rs1800012 single-nucleotide polymorphism (SNP)* of collagen type 1 alpha 1 gene and either stress urinary incontinence (SUI) or pelvic organ prolapse (POP). *RefSNP alleles G/T. Plot presented as risk associated with minor allele T.
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      Two studies of Polish
      • Skorupski P.
      • Król J.
      • Starega J.
      • Adamiak A.
      • Jankiewicz K.
      • Rechberger T.
      An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence.
      and Greek
      • Sioutis D.
      • Economou E.
      • Lambrinoudaki I.
      • Tsamadias V.
      • Creatsa M.
      • Liapis A.
      Sp1 collagen I A1 polymorphism in women with stress urinary incontinence.
      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 (I2 = 0%). There was significant deviation from Hardy-Weinberg equilibrium in one sample,
      • Skorupski P.
      • Król J.
      • Starega J.
      • Adamiak A.
      • Jankiewicz K.
      • Rechberger T.
      An alpha-1 chain of type I collagen Sp1-binding site polymorphism in women suffering from stress urinary incontinence.
      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.
      • Lammers K.
      • Lince S.L.
      • Spath M.A.
      • et al.
      Pelvic organ prolapse and collagen-associated disorders.
      Collagen, type 3 has a particular function in tissue repair, and is typically overexpressed in pelvic tissues from women with prolapse.
      • Chen B.
      • Yeh J.
      Alterations in connective tissue metabolism in stress incontinence and 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
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Wang J.C.
      • Tsai F.J.
      • Tsai C.H.
      Collagen type 3 alpha 1 polymorphism and risk of pelvic organ prolapse.
      and Dutch
      • Lince S.L.
      • van Kempen L.C.
      • Dijkstra J.R.
      • IntHout J.
      • Vierhout M.E.
      • Kluivers K.B.
      Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G>A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population.
      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).
      Figure thumbnail gr4
      Figure 4Forest plot of COL3A1 SNPs and prolapse
      Forest plot of studies
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Wang J.C.
      • Tsai F.J.
      • Tsai C.H.
      Collagen type 3 alpha 1 polymorphism and risk of pelvic organ prolapse.
      • Lince S.L.
      • van Kempen L.C.
      • Dijkstra J.R.
      • IntHout J.
      • Vierhout M.E.
      • Kluivers K.B.
      Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G>A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population.
      • Jeon M.J.
      • Chung S.M.
      • Choi J.R.
      • Jung H.J.
      • Kim S.K.
      • Bai S.W.
      The relationship between COL3A1 exon 31 polymorphism and pelvic organ prolapse.
      • Martins K de F.
      • de Jármy-DiBella Z.I.K.
      • da Fonseca A.M.R.M.
      • et al.
      Evaluation of demographic, clinical characteristics, and genetic polymorphism as risk factors for pelvic organ prolapse in Brazilian women.
      reporting associations between rs1800255* and rs111929073* single-nucleotide polymorphisms (SNPs) of collagen type 3, alpha 1 gene and pelvic organ prolapse with either fixed or random effects models**. *For both SNPs RefSNP alleles A/G. Plot presented as risk associated with minor allele A. **Mantel-Haenszel fixed effects model (M-H)/DerSimonian and Laird random effects model (D+L).
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      For rs111929073, separate Korean
      • Jeon M.J.
      • Chung S.M.
      • Choi J.R.
      • Jung H.J.
      • Kim S.K.
      • Bai S.W.
      The relationship between COL3A1 exon 31 polymorphism and pelvic organ prolapse.
      and Brazilian
      • Martins K de F.
      • de Jármy-DiBella Z.I.K.
      • da Fonseca A.M.R.M.
      • et al.
      Evaluation of demographic, clinical characteristics, and genetic polymorphism as risk factors for pelvic organ prolapse in Brazilian women.
      samples demonstrated a nonsignificant pooled effect (OR, 0.56; 95% CI, 0.19–1.61) (Figure 4) with high heterogeneity (I2 = 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.
      • Nikolova G.
      • Lee H.
      • Berkovitz S.
      • et al.
      Sequence variant in the laminin gamma1 (LAMC1) gene associated with familial pelvic organ prolapse.
      We identified 3 further studies all from the United States that attempted to replicate this initial report of an association with rs10911193,
      • Wu J.M.
      • Visco A.G.
      • Grass E.A.
      • et al.
      Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.
      • Chen C.
      • Hill L.D.
      • Schubert C.M.
      • Strauss J.F.
      • Matthews C.A.
      Is laminin gamma-1 a candidate gene for advanced pelvic organ prolapse?.
      • Fu R.
      • Hagstrom S.
      • Daneshgari F.
      Mutation screen of lysyl oxidase-like-1 and laminin gamma 1 variant in patients with advanced pelvic organ prolapse.
      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
      • Wu J.M.
      • Visco A.G.
      • Grass E.A.
      • et al.
      Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.
      • Chen C.
      • Hill L.D.
      • Schubert C.M.
      • Strauss J.F.
      • Matthews C.A.
      Is laminin gamma-1 a candidate gene for advanced pelvic organ prolapse?.
      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.
      Figure thumbnail gr5
      Figure 5Forest plot of LAMC1 SNPs and prolapse
      Forest plot of studies
      • Wu J.M.
      • Visco A.G.
      • Grass E.A.
      • et al.
      Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.
      • Chen C.
      • Hill L.D.
      • Schubert C.M.
      • Strauss J.F.
      • Matthews C.A.
      Is laminin gamma-1 a candidate gene for advanced pelvic organ prolapse?.
      • Fu R.
      • Hagstrom S.
      • Daneshgari F.
      Mutation screen of lysyl oxidase-like-1 and laminin gamma 1 variant in patients with advanced pelvic organ prolapse.
      reporting associations among rs10911193, rs20563, and rs20558 single-nucleotide polymorphisms (SNPs) of laminin gamma 1 gene and pelvic organ prolapse. *African American subsample. **White subsample. rs10911193 RefSNP alleles C/T. Plot presented as risk associated with minor allele T. rs20563 RefSNP alleles A/G. Plot presented as risk associated with minor allele A. rs20558 RefSNP alleles C/T. Plot presented as risk associated with minor allele C.
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.

      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.
      • Chen B.
      • Yeh J.
      Alterations in connective tissue metabolism in stress incontinence and prolapse.
      Common variants of this gene have been extensively studied in association with chronic obstructive pulmonary disease,
      • Chen L.
      • Wang T.
      • Liu L.
      • Shen Y.
      • Wan C.
      • Wen F.
      Matrix metalloproteinase-9 -1562C/T promoter polymorphism confers risk for COPD: a meta-analysis.
      cardiovascular disease,
      • Li M.
      • Shi J.
      • Fu L.
      • Wang H.
      • Zhou B.
      • Wu X.
      Genetic polymorphism of MMP family and coronary disease susceptibility: a meta-analysis.
      and a number of cancers including of lung, colon, and breast. We identified 2 unpublished studies from the United States,

      Campeau L, Gorbachinsky I, Stancill J, Rohazinski J, Andersson KE. Characterization of SNPs within the MMP-1 promotor region in women with and without POP. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 31, 2011; Glasgow, United Kingdom.

      Vishwajit S, Rohozinski J, Badlani G, Andersson K-E. Association of MMP1 promoter variant with stress urinary incontinence and pelvic organ prolapse in women. Presented as a poster at: the International Continence Society Annual Meeting; Oct. 3, 2009; San Francisco, CA.

      and 2 published studies of Polish
      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      • Skorupski P.
      • Jankiewicz K.
      • Miotła P.
      • Marczak M.
      The polymorphisms of the MMP-1 and the MMP-3 genes and the risk of pelvic organ prolapse.
      and Italian
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      samples assessing associations between MMP1 variants and stress incontinence or prolapse. Of these, 2 studies reported on rs1799750 in association with prolapse,
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      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).
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      For the 2 studies testing associations with SUI,

      Vishwajit S, Rohozinski J, Badlani G, Andersson K-E. Association of MMP1 promoter variant with stress urinary incontinence and pelvic organ prolapse in women. Presented as a poster at: the International Continence Society Annual Meeting; Oct. 3, 2009; San Francisco, CA.

      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      the pooled effect was again nonsignificant (OR, 0.87; 95% CI, 0.63–1.20), with no heterogeneity.
      Figure thumbnail gr6
      Figure 6Forest plot of rs1799750 SNP of MMP1
      Forest plot of studies
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.

      Vishwajit S, Rohozinski J, Badlani G, Andersson K-E. Association of MMP1 promoter variant with stress urinary incontinence and pelvic organ prolapse in women. Presented as a poster at: the International Continence Society Annual Meeting; Oct. 3, 2009; San Francisco, CA.

      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      reporting associations between rs1799750* single-nucleotide polymorphism (SNP) of matrix metalloproteinase 1 (MMP1) gene and either stress urinary incontinence (SUI) or pelvic organ prolapse (POP) with either fixed or random effects models. ∗RefSNP Alleles -/G. Plot presented as risk associated with minor deletion allele.
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.

      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,
      • Li M.
      • Shi J.
      • Fu L.
      • Wang H.
      • Zhou B.
      • Wu X.
      Genetic polymorphism of MMP family and coronary disease susceptibility: a meta-analysis.
      and a number of cancers. We identified 2 studies again of women of European descent,
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      • Skorupski P.
      • Miotla P.
      • Jankiewicz K.
      • Rechberger T.
      MMP-1 and MMP-3 gene encoding polymorphism and the risk of the development of pelvic organ prolapse and stress urinary incontinence.
      • Skorupski P.
      • Jankiewicz K.
      • Miotła P.
      • Marczak M.
      The polymorphisms of the MMP-1 and the MMP-3 genes and the risk of pelvic organ prolapse.
      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.
      Figure thumbnail gr7
      Figure 7Forest plot of rs3025058 SNP of MMP3 and prolapse
      Forest plot of studies
      • Danforth K.N.
      • Townsend M.K.
      • Lifford K.
      • Curhan G.C.
      • Resnick N.M.
      • Grodstein F.
      Risk factors for urinary incontinence among middle-aged women.
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      reporting associations between rs3025058* single-nucleotide polymorphism (SNP) of matrix metalloproteinase 3 gene and pelvic organ prolapse. *RefSNP Alleles -/T. Plot presented as risk associated with minor deletion allele.
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.

      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.
      • Wu J.M.J.
      • Visco A.G.A.
      • Grass E.A.E.
      • et al.
      Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse.
      Like MMP1 and MMP3, its common polymorphisms have been linked to chronic obstructive pulmonary disease,
      • Chen L.
      • Wang T.
      • Liu L.
      • Shen Y.
      • Wan C.
      • Wen F.
      Matrix metalloproteinase-9 -1562C/T promoter polymorphism confers risk for COPD: a meta-analysis.
      cardiovascular disease,
      • Li M.
      • Shi J.
      • Fu L.
      • Wang H.
      • Zhou B.
      • Wu X.
      Genetic polymorphism of MMP family and coronary disease susceptibility: a meta-analysis.
      and some cancers. We identified 4 studies of Italian,
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      Taiwanese,
      • Chen H.Y.
      • Lin W.Y.
      • Chen Y.H.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Matrix metalloproteinase-9 polymorphism and risk of pelvic organ prolapse in Taiwanese women.
      and white US
      • Wu J.M.J.
      • Visco A.G.A.
      • Grass E.A.E.
      • et al.
      Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse.
      • Romero A.
      • Jamison M.
      Are single nucleotide polymorphisms associated with pelvic organ prolapse?.
      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 (I2 = 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
      • Chen H.Y.
      • Lin W.Y.
      • Chen Y.H.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Matrix metalloproteinase-9 polymorphism and risk of pelvic organ prolapse in Taiwanese 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.
      Figure thumbnail gr8
      Figure 8Forest plot of MM9 SNPs and prolapse
      Forest plot of studies
      • Ferrari M.M.
      • Rossi G.
      • Biondi M.L.
      • Viganò P.
      • Dell’Utri C.
      • Meschia M.
      Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse.
      • Wu J.M.J.
      • Visco A.G.A.
      • Grass E.A.E.
      • et al.
      Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse.
      • Chen H.Y.
      • Lin W.Y.
      • Chen Y.H.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Matrix metalloproteinase-9 polymorphism and risk of pelvic organ prolapse in Taiwanese women.
      • Romero A.
      • Jamison M.
      Are single nucleotide polymorphisms associated with pelvic organ prolapse?.
      reporting associations between rs3918242* and rs17576** single-nucleotide polymorphisms (SNPs) of matrix metalloproteinase 9 gene and pelvic organ prolapse with either fixed or random effects models⌘. *rs3918242 RefSNP alleles C/T. Plot presented as risk associated with minor allele T. **rs17576 RefSNP alleles A/G. Plot presented as risk associated with minor allele A. ⌘Mantel-Haenszel fixed effects model (M-H)/DerSimonian and Laird random effects model (D+L).
      CI, confidence interval; OR, odds ratio.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.

      Publication bias and selective analysis

      Each metaanalysis included at most 4 studies or subgroups, providing low power for conventional measures of funnel plot asymmetry. The Harbord test demonstrated no evidence of small study bias or publication bias (all P > .1). We applied the significance chasing bias test,
      • Ioannidis J.P.A.
      • Trikalinos T.A.
      An exploratory test for an excess of significant findings.
      to look for further evidence of publication bias or selective outcome reporting. This exploratory test is used to detect an excess of significant results, either within a single metaanalysis, or in a whole domain of research. In common with other tests of publication bias, P < .1 is usually taken as the threshold for significance. We applied the test across each of the 13 metaanalyses conducted individually, and for the 13 considered together as 1 domain. Given the power of the individual studies to detect the observed pooled effect sizes in each metaanalysis, across the domain as a whole we expected 6.61 statistically significant studies, and observed 7 significant studies in our own prespecified reanalyses using the allelic test (P = .87). However, primary publications applied a variety of analytic techniques, and from the set of studies included in metaanalysis we observed 11 studies reporting statistically significant results in their own analyses (P = .14), typically using alternative models of inheritance. These findings are suggestive primarily of selective analysis, rather than publication bias. Individual metaanalyses again provided limited power for this test, but possible bias was most apparent in the quantitative synthesis of association of prolapse with the rs17576 SNP of MMP9 (P = .11).

      Genes and/or polymorphisms reported in a single study

      Among the included studies, some had assessed associations with polymorphisms for which no replication has been reported. Statistically significant associations have been suggested between prolapse and the rs2228480 polymorphism of ESR1, the estrogen receptor alpha
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Estrogen receptor alpha polymorphism is associated with pelvic organ prolapse risk.
      ; between prolapse and certain haplotypes of ESR2, the estrogen receptor beta
      • Chen H.Y.
      • Wan L.
      • Chung Y.W.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Estrogen receptor beta gene haplotype is associated with pelvic organ prolapse.
      ; between prolapse and the rs484389 polymorphism of PGR, the progesterone receptor
      • Chen H.Y.
      • Chung Y.W.
      • Lin W.Y.
      • Chen W.C.
      • Tsai F.J.
      • Tsai C.H.
      Progesterone receptor polymorphism is associated with pelvic organ prolapse risk.
      ; between prolapse and the rs10478694 polymorphism of EDN1, endothelin 1

      Choy KW, Wong ASW, Cheon WC, et al. Genetic association study in women with pelvic organ prolapse. Presented as a poster at: the International Continence Society Annual Meeting; Aug. 24, 2007; Rotterdam, The Netherlands.

      ; between incontinence and the CAG copy number variant of AR, the androgen receptor
      • Cornu J.N.
      • Merlet B.
      • Cussenot O.
      • et al.
      Genetic susceptibility to urinary incontinence: implication of polymorphisms of androgen and estrogen pathways.
      ; between incontinence and the rs6313 polymorphism of HTR2A, the serotonin 2A receptor
      • Noronha J.A.
      • Schwanke C.H.
      • Machado D.C.
      • et al.
      Association between T102C polymorphism of serotonin 2A receptor gene and urinary incontinence in older women.
      ; between stress incontinence and both the rs2165241 and rs1048661 variants of LOX-L1, lysyloxidaselike-1
      • Ozbek E.
      • Polat E.C.
      • Ozcan L.
      • Otunctemur A.
      • Emrence Z.
      • Ustek D.
      TT polymorphism in rs2165241 and rs1048661 region in lysyl oxidase like-1 gene may have a role in stress urinary incontinence physiopathology.
      ; between the rs1136410 polymorphism of poly-ADP ribose polymerase (PARP)
      • Kim J.Y.
      • Kim E.J.
      • Jeon M.J.
      • Kim H.
      • Moon Y.J.
      • Bai S.W.
      Association between the poly(ADP-ribose) polymerase-1 gene polymorphism and advanced pelvic organ prolapse.
      and prolapse; and finally between the rs1695 polymorphism of glutathione S-transferase pi (GSTP1) and prolapse.
      • Kim J.Y.
      • Kim E.J.
      • Jeon M.J.
      • Kim R.
      • Lee M.W.
      • Kim S.W.
      Association between susceptibility to advanced pelvic organ prolapse and glutathione S-transferase P1 Ile105Val polymorphism.
      We found only 1 published study reporting entirely nonsignificant results,
      • Ferrell G.
      • Lu M.
      • Stoddard P.
      • et al.
      A single nucleotide polymorphism in the promoter of the LOXL1 gene and its relationship to pelvic organ prolapse and preterm premature rupture of membranes.
      further suggesting a high probability of selective outcome reporting or publication bias for this field of study as a whole. Following the Venice recommendations,
      • Harris R.J.
      • Bradburn M.J.
      • Deeks J.J.
      • et al.
      Metan: fixed- and random-effects meta-analysis.
      we a priori assigned all nominally significant but unreplicated associations weak epidemiological credibility. Three genome-wide association studies (GWAS) have now been reported for incontinence or prolapse.
      • Allen-Brady K.
      • Cannon-Albright L.
      • Farnham J.M.
      • et al.
      Identification of six loci associated with pelvic organ prolapse using genome-wide association analysis.

      Velez Edwards DR, Ward RM, Giri A, et al. Trans-ethnic GWAS of pelvic organ prolapse among African American and Hispanic postmenopausal women of the Women's Health Initiative. Presented as a poster at: the American Society of Human Genetics Annual Meeting; Oct. 25, 2013; Boston, MA.

      Chen C, Rajkovic A, Park A, Heiss G, Hendrix S, Franceschini N. Uncovering loci associated with urinary incontinence in African and Hispanic American women. Presented as a poster at: the American Society of Human Genetics Annual Meeting; Oct. 25, 2013; Boston, MA.

      Of note, none of these suggested candidates for prolapse or incontinence, including both those from single studies, as well as those included in metaanalyses, were identified in these genome-wide analyses. Across the 3 GWAS, SNPs at 9 independent loci have reached genome-wide significance (P < 5 × 10-8) (Table 1) in discovery cohorts, although replication of these candidate loci has not been demonstrated.

      Comment

      Strengths and limitations

      The strengths of this review include a comprehensive search of both published and unpublished studies, applying explicit criteria to potentially eligible studies, and employing standardized, piloted data forms for data collection, guided by written instructions, and an unbiased assessment and synthesis of reported associations. We followed a prespecified data analysis plan, and contacted authors for clarifications and additional data.
      Among the challenges faced in this review was the inclusion of studies with varying diagnostic criteria. There may be considerable disparity between symptomatic and objective findings for both LUTS and prolapse, and despite long-standing efforts for standardization
      • Haylen B.T.
      • De Ridder D.
      • Freeman R.M.
      • et al.
      An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction.
      diagnostic criteria are not widely agreed upon. Despite this caution, we found that the literature had used largely concordant definitions. From the prolapse studies, 2 studies had used a prolapse case definition based on need for surgical treatment, but all others used an accepted anatomic staging system, typically POP Quantification. There was also little variation in cutoffs for significant prolapse, with almost all studies considering prolapse stage 0 or stage 1 as normal/control. Both overactive bladder studies included in metaanalysis used a combination of self-reported symptoms, with 3-day bladder diary for diagnosis. Similarly both SUI studies included in metaanalysis used a combination of cystometry and pad testing for diagnosis. This is reflected in a lack of heterogeneity in most metaanalyses. Regardless of the presence of statistical heterogeneity, there remains potential for bias toward the null from heterogeneity in case definitions.
      It is evident that overactive bladder in particular may have multiple underlying causes,
      • Herschorn S.
      Overactive bladder: symptom complex or separate entity?.
      • Tikkinen K.A.
      • Auvinen A.
      Does the imprecise definition of overactive bladder serve commercial rather than patient interests?.
      and these syntheses may therefore include participants with diverse underlying etiologies for their symptoms. The largest metaanalyses possible still include <1000 participants in total, and therefore provide adequate power only for associations with large effect size (approximately OR, ≤0.6 or OR, ≥1.8). It is both likely that smaller effect sizes have been missed in these syntheses, and highly probable that polymorphisms with larger effect sizes are still to be discovered.

      Future work

      Future advances are likely within the context of GWAS using large-scale population-based cohorts phenotyped for these conditions. The discovery of further causative variants should both help to explain the complex pathophysiology of these conditions, and provide potentially a route to effective prevention and treatment.

      Conclusions

      Family and twin studies have provided convincing evidence for genetic predisposition to incontinence, prolapse, and overactive bladder, with genetic variation contributing up to half of population phenotypic variability. These metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and COL1A1 with prolapse. As for all complex diseases, these 2 currently identified polymorphisms explain a tiny fraction of that phenotypic variation. The widespread availability of direct-to-consumer testing means that some patients may present with questions about the implications of these polymorphisms. However, testing for any of these SNPs cannot be recommended based on current evidence. Nevertheless, clinicians and researchers should be aware of the putative risks associated with these SNPs, and the uncertainty regarding potential biases in the primary studies. In the future, genetic counseling may play one part of advice about risks of mode of delivery, and may help target women for primary or secondary prevention. Currently, clinicians should continue to use a family history of prolapse or incontinence as a simple marker of future risk, with clearly documented interactions with modifiable risk factors such as vaginal childbirth and obesity.

      Appendix

      Figure thumbnail fx1
      Supplementary FigureSummary of interim Venice guideline ratings of credibility of genetic associations
      Adapted and abridged from Ioannidis et al.
      • Ioannidis J.P.
      • Boffetta P.
      • Little J.
      • et al.
      Assessment of cumulative evidence on genetic associations: interim guidelines.
      Strong credibility for association requires AAA rating. Any B rating confers maximum moderate credibility, while any C rating confers weak credibility.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      Supplementary Table 1Functional annotation of investigated genes
      Official gene symbolGene name(s)No. of studies includedMolecular function(s)
      ADRA1AAdrenergic, alpha-1A-, receptor1Adrenoceptor activity

      Alpha-adrenergic receptor activity

      Alpha1-adrenergic receptor activity

      Amine receptor activity
      ADRB3Adrenergic, beta-3-, receptor3Adrenoceptor activity

      Beta-adrenergic receptor activity

      Amine receptor activity

      Beta-3-adrenergic receptor activity

      Adrenergic receptor binding

      Beta-3 adrenergic receptor binding

      Identical protein binding

      Protein homodimerization activity

      Amine binding

      Alcohol binding

      Protein dimerization activity

      Epinephrine binding

      Norepinephrine binding
      ARAndrogen receptor1DNA binding

      Transcription factor activity

      Steroid hormone receptor activity

      Ligand-dependent nuclear receptor activity

      Androgen receptor activity

      Steroid binding

      Androgen binding

      Zinc ion binding

      Lipid binding

      Transcription activator activity

      Transcription regulator activity

      Hormone binding

      Ion binding

      Cation binding

      Sequence-specific DNA binding

      Metal ion binding

      Transition metal ion binding

      Protein dimerization activity
      COL1A1Collagen, type I, alpha 17Structural molecule activity

      Extracellular matrix structural constituent

      Growth factor binding

      Identical protein binding

      Platelet-derived growth factor binding,
      COL3A1Collagen, type III, alpha 14Integrin binding

      Structural molecule activity

      Extracellular matrix structural constituent

      Growth factor binding

      Protein complex binding

      SMAD binding

      Platelet-derived growth factor binding
      COL18A1Collagen, type XVIII, alpha 11Structural molecule activity

      Extracellular matrix structural constituent

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding
      CPECarboxypeptidase E1Metallocarboxypeptidase activity

      Zinc ion binding
      CYP17A1Cytochrome P450, family 17, subfamily A, polypeptide 11Steroid 17-alpha-monooxygenase activity

      Iron ion binding

      Steroid hydroxylase activity

      Electron carrier activity

      Oxygen binding

      Heme binding

      Ion binding

      Cation binding

      Metal ion binding

      Tetrapyrrole binding

      Transition metal ion binding
      CYP19A1Cytochrome P450, family 19, subfamily A, polypeptide 11Iron ion binding

      Electron carrier activity

      Oxidoreductase activity

      Oxygen binding

      Heme binding

      Ion binding

      Cation binding

      Metal ion binding

      Tetrapyrrole binding

      Transition metal ion binding

      Aromatase activity
      EDN1Endothelin 11Hormone activity

      Bombesin receptor binding

      Endothelin A receptor binding

      Endothelin B receptor binding
      ESR1Estrogen receptor 11DNA binding

      Transcription factor activity

      Steroid hormone receptor activity

      Ligand-dependent nuclear receptor activity

      Steroid binding

      Zinc ion binding

      Lipid binding

      Promoter binding

      Nitric-oxide synthase regulator activity

      Estrogen receptor activity

      Transcription regulator activity

      Estrogen response element binding

      Hormone binding

      Ion binding

      Cation binding

      Sequence-specific DNA binding

      Metal ion binding transition

      Metal ion binding

      Protein N-terminus binding
      ESR2Estrogen receptor 2 (ER beta)1DNA binding

      Transcription factor activity

      Steroid hormone receptor activity

      Transcription cofactor activity

      Transcription coactivator activity

      Ligand-dependent nuclear receptor activity

      Steroid binding transcription factor binding

      Zinc ion binding

      Lipid binding

      Transcription activator activity

      Estrogen receptor activity

      Transcription regulator activity

      Receptor regulator activity

      Receptor inhibitor activity

      Hormone binding

      Ion binding

      Cation binding

      Sequence-specific DNA binding

      Metal ion binding

      Transition metal ion binding

      Receptor antagonist activity
      GSTM1Glutathione S-transferase mu 11Glutathione transferase activity
      GSTP1Glutathione S-transferase pi 11Glutathione transferase activity
      GSTT1Glutathione S-transferase theta 11Glutathione transferase activity
      HTR2A5-Hydroxytryptamine (serotonin) receptor 2A1Serotonin receptor activity

      Amine receptor activity

      Protein complex binding

      Amine binding

      Serotonin binding
      LAMC1Laminin, gamma 1 (formerly LAMB2)3Structural molecule activity

      Extracellular matrix structural constituent,
      LOXL1Lysyl oxidase-like 13Copper ion binding

      Oxidoreductase activity

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding
      MMP1Matrix metallopeptidase 1 (interstitial collagenase)5Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      MMP10Matrix metallopeptidase 10 (stromelysin 2)1Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      MMP11Matrix metallopeptidase 11 (stromelysin 3)1Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      MMP2Matrix metallopeptidase 2 (gelatinase A, 72-kDa gelatinase, 72-kDa type IV collagenase)1Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      MMP3Matrix metallopeptidase 3 (stromelysin 1, progelatinase)3Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      MMP8Matrix metallopeptidase 8 (neutrophil collagenase)1Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      MMP9Matrix metallopeptidase 9 (gelatinase B, 92-kDa gelatinase, 92-kDa type IV collagenase)4Endopeptidase activity

      Metalloendopeptidase activity

      Calcium ion binding

      Peptidase activity

      Metallopeptidase activity

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding

      Peptidase activity

      Acting on L-amino acid peptides
      PARP1Poly (ADP-ribose) polymerase 11Telomere maintenance

      DNA repair

      Transcription

      Chromosome organization
      PGRProgesterone receptor1DNA binding transcription factor activity

      Steroid hormone receptor activity

      Ligand-dependent nuclear receptor activity

      Steroid binding

      Zinc ion binding

      Lipid binding

      Transcription regulator activity

      Ion binding

      Cation binding

      Sequence-specific DNA binding

      Metal ion binding

      Transition metal ion binding

      Protein N-terminus binding
      PRCPProlylcarboxypeptidase (angiotensinase C)1Carboxypeptidase activity

      Serine hydrolase activity
      TIMP1TIMP metallopeptidase inhibitor 11Enzyme inhibitor activity,

      Endopeptidase inhibitor activity

      Metalloendopeptidase inhibitor activity

      Metalloenzyme regulator activity

      Peptidase inhibitor activity

      Metalloenzyme inhibitor activity
      TIMP3TIMP metallopeptidase inhibitor 31Enzyme inhibitor activity

      Endopeptidase inhibitor activity

      Metalloendopeptidase inhibitor activity

      Metalloenzyme regulator activity

      Peptidase inhibitor activity

      Metalloenzyme inhibitor activity
      ZFATZinc finger and AT hook domain containing1DNA binding

      Zinc ion binding

      Ion binding

      Cation binding

      Metal ion binding

      Transition metal ion binding
      Functions assigned from http://david.abcc.ncifcrf.gov.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.
      Supplementary Table 2Overrepresented Gene Ontology biological processes among investigated genes
      Biological processGO termDescriptionGenes
      1GO:0030574Collagen catabolic processMMP1 MMP2 MMP3 MMP8 MMP9 MMP10 MMP11
      2GO:0005578Proteinaceous extracellular matrixLOXL1 MMP1 MMP2 MMP3 MMP8 MMP9 MMP10 MMP11 TIMP1
      3GO:0006508ProteolysisCPE MMP1 MMP2 MMP3 MMP8 MMP9 MMP10 MMP11 PRCP
      4GO:0008152Metabolic processCPE GSTM1 MMP2 MMP8 MMP3 GSTP1 MMP1 MMP10 MMP9
      5GO:0005576Extracellular regionCOL1A1 COL3A1 CPE EDN1 ESR2 LAMC1 LOXL1 MMP1 MMP2 MMP3 MMP8 MMP9 MMP10 MMP11 TIMP1 COL18A1
      6GO:0007267Cell-cell signallingPGR AR ADRA1A ESR2 EDN1
      7GO:0005615Extracellular spaceAR COL1A1 COL3A1 EDN1 LAMC1 LOXL1 MMP2 MMP3 MMP8 MMP9 MMP10 COL18A1
      8GO:0008270Zinc ion bindingESR1 ESR2 MMP1 MMP2 MMP3 MMP8 MMP9 MMP10 MMP11 PGR ZFAT
      All processes significant at P < .01, analysis using http://webclu.bio.wzw.tum.de/profcom/. Overrepresented Gene Ontology: http://www.geneontology.org.
      Cartwright. Genetic association studies of LUTS and POP. Am J Obstet Gynecol 2015.

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