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

Abstract

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 In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes.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

Keywords: genetics; incontinence; lower urinary tract symptoms; overactive bladder; prolapse; systematic review.

Supplementary Figure

Summary of interim Venice guideline ratings of credibility of genetic associations 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.

Figure 1

Flowchart 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.

Figure 2

Forest plot of rs4994 SNP of ADRB3 and overactive bladder Forest plot of studies 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.

Figure 3

Forest plot of studies of rs1800013 SNP of COL1A1 Forest plot of studies 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.

Figure 4

Forest plot of COL3A1 SNPs and prolapse Forest plot of studies 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.

Figure 5

Forest plot of LAMC1 SNPs and prolapse Forest plot of studies 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.

Figure 6

Forest plot of rs1799750 SNP of MMP1 Forest plot of studies 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.

Figure 7

Forest plot of rs3025058 SNP of MMP3 and prolapse Forest plot of studies 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.

Figure 8

Forest plot of MM9 SNPs and prolapse Forest plot of studies 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.