Skip to main content

Advertisement

SpringerLink
Log in

Gene expression in stress urinary incontinence: a systematic review

  • Review Article
  • Published:
International Urogynecology Journal Aims and scope Submit manuscript

Abstract

Introduction

A contribution of genetic factors to the development of stress urinary incontinence (SUI) is broadly acknowledged. This study aimed to: (1) provide insight into the genetic pathogenesis of SUI by gathering and synthesizing the available data from studies evaluating differential gene expression in SUI patients and (2) identify possible novel therapeutic targets and leads.

Methods

A systematic literature search was conducted through September 2017 for the concepts of genetics and SUI. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in SUI were performed using GeneMANIA software.

Results

Of 3019 studies, 4 were included in the final analysis. A total of 13 genes were identified as being differentially expressed in SUI patients. Eleven genes were overexpressed: skin-derived antileukoproteinase (SKALP/elafin), collagen type XVII alpha 1 chain (COL17A1), plakophilin 1 (PKP1), keratin 16 (KRT16), decorin (DCN), biglycan (BGN), protein bicaudal D homolog 2 (BICD2), growth factor receptor-bound protein 2 (GRB2), signal transducer and activator of transcription 3 (STAT3), apolipoprotein E (APOE), and Golgi SNAP receptor complex member 1 (GOSR1), while two genes were underexpressed: fibromodulin (FMOD) and glucocerebrosidase (GBA). GeneMANIA revealed that these genes are involved in intermediate filament cytoskeleton and extracellular matrix organization.

Conclusion

Many genes are involved in the pathogenesis of SUI. Furthermore, whole-genome studies are warranted to identify these genetic connections. This study lays the groundwork for future research and the development of novel therapies and SUI biomarkers in clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

SUI :

Stress urinary incontinence

POP :

Pelvic organ prolapse

PRISMA :

Preferred Reporting Items for Systematic Reviews

IF :

Immunofluorescence staining

COL17A1 :

Collagen type XVII alpha chain

SKALP :

Skin-derived antileukoproteinase

KRT16 :

Keratin 16

STAT3 :

Signal transducer and activator of transcription 3

DCN :

Decorin

SNARE :

Soluble NSF attachment protein receptor

APOE :

Apolipoprotein E

GBA :

Glucocerebrosidase

PCR :

Polymerase chain reaction

POP-Q :

Pelvic organ prolapse quantification

GeneMANIA :

Gene multiple association network integration algorithms

IHC :

Immunohistochemistry

PKP1 :

Plakophilin 1

GRB2 :

Growth factor receptor-bound protein 2

BICD2 :

Protein bicaudal D homolog 2

BGN :

Biglycan

GOSR1 :

Golgi SNAP receptor complex member 1

FMOD :

Fibromodulin

References

  1. Sangsawang B, Sangsawang N. Stress urinary incontinence in pregnant women: a review of prevalence, pathophysiology, and treatment. Int Urogynecol J. 2013;24(6):901–12. https://doi.org/10.1007/s00192-013-2061-7.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kwon CS, Lee JH. Prevalence, risk factors, quality of life, and health-care seeking behaviors of female urinary incontinence: results from the 4th Korean National Health and nutrition examination survey VI (2007-2009). Int Neurourol J. 2014;18(1):31–6. https://doi.org/10.5213/inj.2014.18.1.31.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Khalifa AO, Kavran M, Mahran A, Isali I, Woda J, Flask CA, et al. Stromal derived factor-1 plasmid as a novel injection for treatment of stress urinary incontinence in a rat model. Int Urogynecol J. 2019. https://doi.org/10.1007/s00192-019-03867-3.

  4. Gigliobianco G, Regueros SR. Biomaterials for pelvic floor reconstructive surgery: how can we do better?. 2015; 2015:968087. doi:https://doi.org/10.1155/2015/968087.

    Article  Google Scholar 

  5. Ninomiya S, Naito K, Nakanishi K, Okayama H. Prevalence and risk factors of urinary incontinence and overactive bladder in Japanese women. Lower Urinary Tract Symp. 2017. https://doi.org/10.1111/luts.12185.

    PubMed  Google Scholar 

  6. Rikard-Bell J, Iyer J, Rane A. Perineal outcome and the risk of pelvic floor dysfunction: a cohort study of primiparous women. Aust N Z J Obstet Gynaecol. 2014;54(4):371–6. https://doi.org/10.1111/ajo.12222.

    Article  PubMed  Google Scholar 

  7. Hannestad YS, Lie RT, Rortveit G, Hunskaar S. Familial risk of urinary incontinence in women: population based cross sectional study. BMJ (Clinical Res ed). 2004;329(7471):889–91. https://doi.org/10.1136/bmj.329.7471.889.

    Article  Google Scholar 

  8. Skoner MM, Thompson WD, Caron VA. Factors associated with risk of stress urinary incontinence in women. Nurs Res. 1994;43(5):301–6.

    Article  CAS  PubMed  Google Scholar 

  9. McKenzie P, Rohozinski J, Badlani G. Genetic influences on stress urinary incontinence. Curr Opin Urol. 2010;20(4):291–5. https://doi.org/10.1097/MOU.0b013e32833a4436.

    Article  PubMed  Google Scholar 

  10. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jeong SJ, Kim HJ, Lee BK, Rha W, Oh JJ, Jeong CW, et al. Women with pure stress urinary incontinence symptoms assessed by the initial standard evaluation including measurement of post-void residual volume and a stress test: are urodynamic studies still needed? Neurourol Urodyn. 2012;31(4):508–12. https://doi.org/10.1002/nau.21215.

    Article  PubMed  Google Scholar 

  12. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. Newcastle-Ottawa quality assessment Scale, Cohort Studies, 2014.

  13. NHLBI. Quality assessment tool for observational cohort and cross-sectional studies, 2018. https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.

  14. Chen B, Wen Y, Zhang Z, Guo Y, Warrington JA, Polan ML. Microarray analysis of differentially expressed genes in vaginal tissues from women with stress urinary incontinence compared with asymptomatic women. Human Reprod (Oxford, England). 2006;21(1):22–9. https://doi.org/10.1093/humrep/dei276.

    Article  CAS  Google Scholar 

  15. Wen Y, Zhao YY, Li S, Polan ML, Chen BH. Differences in mRNA and protein expression of small proteoglycans in vaginal wall tissue from women with and without stress urinary incontinence. Human Reprod (Oxford, England). 2007;22(6):1718–24. https://doi.org/10.1093/humrep/dem039.

    Article  CAS  Google Scholar 

  16. Liu X, Lang J, Wu S, Cheng L, Wang W, Zhu L. Differential expression of microRNAs in periurethral vaginal wall tissues of postmenopausal women with and without stress urinary incontinence. Menopause (New York, NY). 2014;21(10):1122–8. https://doi.org/10.1097/gme.0000000000000222.

    Article  Google Scholar 

  17. Tong J, Lang J, Zhu L. Microarray analysis of differentially expressed genes in vaginal tissues in postmenopausal women. The role of stress urinary incontinence. Int Urogynecol J. 2010;21(12):1545–51. https://doi.org/10.1007/s00192-010-1222-1.

    Article  PubMed  Google Scholar 

  18. Kuijpers AL, Pfundt R, Zeeuwen PL, Molhuizen HO, Mariman EC, van de Kerkhof PC, et al. SKALP/elafin gene polymorphisms are not associated with pustular forms of psoriasis. Clin Genet. 1998;54(1):96–101.

    Article  CAS  PubMed  Google Scholar 

  19. Vandermeeren M, Daneels G, Bergers M, van Vlijmen-Willems I, Pol A, Geysen J, et al. Development and application of monoclonal antibodies against SKALP/elafin and other trappin family members. Arch Dermatol Res. 2001;293(7):343–9.

    Article  CAS  PubMed  Google Scholar 

  20. van Bergen BH, Andriessen MP, Spruijt KI, van de Kerkhof PC, Schalkwijk J. Expression of SKALP/elafin during wound healing in human skin. Arch Dermatol Res. 1996;288(8):458–62.

    Article  PubMed  Google Scholar 

  21. Wiedow O, Schroder JM, Gregory H, Young JA, Christophers E. Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J Biol Chem. 1990;265(25):14791–5.

    CAS  PubMed  Google Scholar 

  22. Powell AM, Sakuma-Oyama Y, Oyama N, Black MM. Collagen XVII/BP180: a collagenous transmembrane protein and component of the dermoepidermal anchoring complex. Clin Exp Dermatol. 2005;30(6):682–7. https://doi.org/10.1111/j.1365-2230.2005.01937.x.

    Article  CAS  PubMed  Google Scholar 

  23. Hopkinson SB, Findlay K, deHart GW, Jones JC. Interaction of BP180 (type XVII collagen) and alpha6 integrin is necessary for stabilization of hemidesmosome structure. J Investig Dermatol. 1998;111(6):1015–22. https://doi.org/10.1046/j.1523-1747.1998.00452.x.

    Article  CAS  PubMed  Google Scholar 

  24. Varki R, Sadowski S, Pfendner E, Uitto J. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. J Med Genet. 2006;43(8):641–52. https://doi.org/10.1136/jmg.2005.039685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sobolik-Delmaire T, Reddy R, Pashaj A, Roberts BJ, Wahl JK 3rd. Plakophilin-1 localizes to the nucleus and interacts with single-stranded DNA. J Investig Dermatol. 2010;130(11):2638–46. https://doi.org/10.1038/jid.2010.191.

    Article  CAS  PubMed  Google Scholar 

  26. Sprecher E, Molho-Pessach V, Ingber A, Sagi E, Indelman M, Bergman R. Homozygous splice site mutations in PKP1 result in loss of epidermal plakophilin 1 expression and underlie ectodermal dysplasia/skin fragility syndrome in two consanguineous families. J Investig Dermatol. 2004;122(3):647–51. https://doi.org/10.1111/j.0022-202X.2004.22335.x.

    Article  CAS  PubMed  Google Scholar 

  27. Yang C, Fischer-Keso R, Schlechter T, Strobel P, Marx A, Hofmann I. Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression. Tumour Biol : J Int Soc Oncodev Biol Med. 2015;36(12):9567–77. https://doi.org/10.1007/s13277-015-3628-3.

    Article  CAS  Google Scholar 

  28. Lessard JC, Pina-Paz S, Rotty JD, Hickerson RP, Kaspar RL, Balmain A, et al. Keratin 16 regulates innate immunity in response to epidermal barrier breach. Proc Natl Acad Sci U S A. 2013;110(48):19537–42. https://doi.org/10.1073/pnas.1309576110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duverger O, Cross MA, Smith FJD, Morasso MI. Enamel anomalies in a pachyonychia congenita patient with a mutation in KRT16. J Investig Dermatol. 2018. https://doi.org/10.1016/j.jid.2018.07.005.

    Article  CAS  PubMed  Google Scholar 

  30. Tajerian M, Hung V, Khan H, Lahey LJ, Sun Y, Birklein F, et al. Identification of KRT16 as a target of an autoantibody response in complex regional pain syndrome. Exp Neurol. 2017;287(Pt 1):14–20. https://doi.org/10.1016/j.expneurol.2016.10.011.

    Article  CAS  PubMed  Google Scholar 

  31. Kalamajski S, Oldberg A. The role of small leucine-rich proteoglycans in collagen fibrillogenesis. Matrix Biol : J Int Soc Matrix Biol. 2010;29(4):248–53. https://doi.org/10.1016/j.matbio.2010.01.001.

    Article  CAS  Google Scholar 

  32. Jarvinen TA, Prince S. Decorin: a growth factor antagonist for tumor growth inhibition. Biomed Res Int. 2015;2015:654765. https://doi.org/10.1155/2015/654765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Svensson L, Heinegard D, Oldberg A. Decorin-binding sites for collagen type I are mainly located in leucine-rich repeats 4-5. J Biol Chem. 1995;270(35):20712–6.

    Article  CAS  PubMed  Google Scholar 

  34. Traupe H, van den Ouweland AM, van Oost BA, Vogel W, Vetter U, Warren ST, et al. Fine mapping of the human biglycan (BGN) gene within the Xq28 region employing a hybrid cell panel. Genomics. 1992;13(2):481–3.

    Article  CAS  PubMed  Google Scholar 

  35. Liu B, Xu T, Xu X, Cui Y, Xing X. Biglycan promotes the chemotherapy resistance of colon cancer by activating NF-kappaB signal transduction. Mol Cell Biochem. 2018. https://doi.org/10.1007/s11010-018-3365-1.

    Article  CAS  PubMed  Google Scholar 

  36. Hu L, Zang MD, Wang HX, Li JF, Su LP, Yan M, et al. Biglycan stimulates VEGF expression in endothelial cells by activating the TLR signaling pathway. Mol Oncol. 2016;10(9):1473–84. https://doi.org/10.1016/j.molonc.2016.08.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martinez Carrera LA, Gabriel E, Donohoe CD, Holker I, Mariappan A, Storbeck M, et al. Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development. Hum Mol Genet. 2018;27(10):1772–84. https://doi.org/10.1093/hmg/ddy086.

    Article  CAS  PubMed  Google Scholar 

  38. Huang X, Fan D. A novel mutation of BICD2 gene associated with juvenile amyotrophic lateral sclerosis. Amyotrophic Later Sclerosis Frontotemp Degen. 2017;18(5-6):454–6. https://doi.org/10.1080/21678421.2017.1304557.

    Article  CAS  Google Scholar 

  39. Yoshioka M, Morisada N, Toyoshima D, Yoshimura H, Nishio H, Iijima K, et al. Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2. Brain Dev. 2018;40(4):343–7. https://doi.org/10.1016/j.braindev.2017.12.001.

    Article  PubMed  Google Scholar 

  40. Roy K, Raychaudhuri M, Chakrabarti O, Mukhopadhyay D. Growth factor receptor-bound protein 2 promotes autophagic removal of amyloid-beta protein precursor intracellular domain overload in neuronal cells. J Alzheimer’s Dis : JAD. 2014;38(4):881–95. https://doi.org/10.3233/jad-130929.

    Article  CAS  Google Scholar 

  41. Majumder P, Roy K, Singh BK, Jana NR, Mukhopadhyay D. Cellular levels of Grb2 and cytoskeleton stability are correlated in a neurodegenerative scenario, 2017. 10 (5):655-669. doi:https://doi.org/10.1242/dmm.027748.

    Article  CAS  Google Scholar 

  42. You L, Wang Z, Li H, Shou J, Jing Z, Xie J, et al. The role of STAT3 in autophagy. Autophagy. 2015;11(5):729–39. https://doi.org/10.1080/15548627.2015.1017192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen X, Chen C, Hao J, Zhang J, Zhang F. Effect of CLIP3 upregulation on astrocyte proliferation and subsequent glial scar formation in the rat spinal cord via STAT3 pathway after injury, 2018. 64 (1):117-128. doi:https://doi.org/10.1007/s12031-017-0998-6.

    Article  PubMed  Google Scholar 

  44. Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008;28(28):7231–43. https://doi.org/10.1523/jneurosci.1709-08.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang X, Chen S, Shao Z, Li Y, Wu H, Li X, et al. Apolipoprotein E deficiency exacerbates spinal cord injury in mice: inflammatory response and oxidative stress mediated by NF-kappaB signaling pathway. Front Cell Neurosci. 2018;12:142. https://doi.org/10.3389/fncel.2018.00142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cheng X, Zheng Y, Bu P, Qi X, Fan C, Li F, et al. Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury. Exp Neurol. 2018;299(Pt A):97–108. https://doi.org/10.1016/j.expneurol.2017.10.014.

    Article  CAS  PubMed  Google Scholar 

  47. Cheng B, Zhang Y, Guo G, Gao Y. Crystallization and preliminary X-ray diffraction analysis of Gos1p, a yeast SNARE protein. Acta Crystallographica Sect F, Struct Biol Commun. 2014;70(Pt 7):967–9. https://doi.org/10.1107/s2053230x14011704.

    Article  CAS  Google Scholar 

  48. Nichols BJ, Pelham HR. SNAREs and membrane fusion in the Golgi apparatus. Biochim Biophys Acta. 1998;1404(1-2):9–31.

    Article  CAS  PubMed  Google Scholar 

  49. Mikaelsson E, Danesh-Manesh AH, Luppert A, Jeddi-Tehrani M, Rezvany MR, Sharifian RA, et al. Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. Blood. 2005;105(12):4828–35. https://doi.org/10.1182/blood-2004-10-3941.

    Article  CAS  PubMed  Google Scholar 

  50. Zheng Z, James AW, Li C, Jiang W, Wang JZ, Chang GX, Lee KS, Chen F, Berthiaume EA, Chen Y, Pan HC, Chen EC, Li W, Zhao Z, Zhang X, Ting K, Soo C. Fibromodulin reduces scar formation in adult cutaneous wounds by eliciting a fetal-like phenotype. Signal transduction and targeted therapy. 2017; 2. doi:https://doi.org/10.1038/sigtrans.2017.50.

  51. Barth BM, Shanmugavelandy SS, Tacelosky DM, Kester M, Morad SA, Cabot MC. Gaucher’s disease and cancer: a sphingolipid perspective. Crit Rev Oncog. 2013;18(3):221–34.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008;29(5):567–83. https://doi.org/10.1002/humu.20676.

    Article  CAS  PubMed  Google Scholar 

  53. Hildebrand A, Romaris M, Rasmussen L, Heinegård D, Twardzik D, Border W, et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor β. Biochem J. 1994;302(2):527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Campeau L, Gorbachinsky I, Badlani GH, Andersson KE. Pelvic floor disorders: linking genetic risk factors to biochemical changes. BJU Int. 2011;108(8):1240–7. https://doi.org/10.1111/j.1464-410X.2011.10385.x.

    Article  CAS  PubMed  Google Scholar 

  55. Lyons MR, West AE. Mechanisms of specificity in neuronal activity-regulated gene transcription. Prog Neurobiol. 2011;94(3):259–95. https://doi.org/10.1016/j.pneurobio.2011.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Britt Conroy, MD PhD JD, is supported by the following funding: National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), K12 Research Scholar, PHS Grant Number 5K12DK 1000014-3, Case Western Reserve University, Cleveland, OH.

Author information

Authors and Affiliations

  1. Department of Urology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Ilaha Isali, Amr Mahran, Ahmad O. Khalifa & Adonis K. Hijaz

  2. Department of Urology, Assiut University, Assiut, Egypt

    Amr Mahran

  3. Department of Urology, Menoufia University, Menoufia, Egypt

    Ahmad O. Khalifa

  4. Department of Obstetrics and Gynecology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    David Sheyn & Sherif A. El-Nashar

  5. Core Library, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Mandy Neudecker

  6. Department of Anesthesiology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Arshna Qureshi

  7. Department of Family Medicine, Metro Health Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Britt Conroy

  8. Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    Fredrick R. Schumacher

Authors
  1. Ilaha Isali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amr Mahran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmad O. Khalifa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Sheyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mandy Neudecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arshna Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Britt Conroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fredrick R. Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adonis K. Hijaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sherif A. El-Nashar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sherif A. El-Nashar.

Ethics declarations

Conflicts of interest

None.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 13.9 kb)

Appendix

Appendix

Table 4 Search strategy
Full size table

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Isali, I., Mahran, A., Khalifa, A.O. et al. Gene expression in stress urinary incontinence: a systematic review. Int Urogynecol J 31, 1–14 (2020). https://doi.org/10.1007/s00192-019-04025-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00192-019-04025-5

Keywords

Search

Navigation