Genetic polymorphisms associated with urinary tract infection in children and adults: a systematic review and meta-analysis.

INTRODUCTION: The lifetime risk of urinary tract infection is known from first-degree relative studies to be highly heritable. Associations have also been observed across the life course from pediatric urinary tract infection to recurrent urinary tract infection in adulthood, suggesting lifelong susceptibility factors. Candidate gene studies and genome-wide association studies have tested for genetic associations of urinary tract infection; however, no contemporary systematic synthesis of studies is available. OBJECTIVE: We conducted a systematic review to identify all genetic polymorphisms tested for an association with urinary tract infection in children and adults; and to assess their strength, consistency, and risk of bias among reported associations. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: PubMed, HuGE Navigator and Embase were searched from January 1, 2005 to November 16, 2023, using a combination of genetic and phenotype key words. STUDY APPRAISAL AND SYNTHESIS METHODS: Fixed and random effects meta-analyses were conducted using codominant models of inheritance in metan. The interim Venice criteria were used to assess their credibility of pooled associations. RESULTS: After removing 451 duplicates, 1821 studies reports were screened, with 106 selected for full-text review, 22 were included in the meta-analysis (7 adult studies and 15 pediatric studies). Our meta-analyses demonstrated significant pooled associations for pediatric urinary tract infection with variation in CXCR1, IL8, TGF, TLR4 and VDR; all of which have plausible roles in the pathogenesis of urinary tract infection. Our meta-analyses also demonstrated a significant pooled association for adult urinary tract infection with variation in CXCR1. All significant pooled associations were graded according to their epidemiological credibility, sample sizes, heterogeneity between studies, and risk of bias. CONCLUSION: This systematic review provides a current synthesis of the known genetic architecture of urinary tract infection in childhood and adulthood; and should provide important information for researchers analysing future genetic association studies. Although, overall, the credibility of pooled associations was weak, the consistency of findings for rs2234671 single nucleotide polymorphisms of CXCR1 in both populations suggest a key role in the urinary tract infection pathogenesis.

International Urogynecological Consultation (IUC): pathophysiology of pelvic organ prolapse (POP).

INTRODUCTION AND HYPOTHESIS: This manuscript is the International Urogynecology Consultation (IUC) on pelvic organ prolapse (POP) chapter one, committee three, on the Pathophysiology of Pelvic Organ Prolapse assessing genetics, pregnancy, labor and delivery, age and menopause and animal models. MATERIALS AND METHODS: An international group of urogynecologists and basic scientists performed comprehensive literature searches using pre-specified terms in selected biomedical databases to summarize the current knowledge on the pathophysiology of the development of POP, exploring specifically factors including (1) genetics, (2) pregnancy, labor and delivery, (3) age and menopause and (4) non-genetic animal models. This manuscript represents the summary of three systematic reviews with meta-analyses and one narrative review, to which a basic scientific comment on the current understanding of pathophysiologic mechanisms was added. RESULTS: The original searches revealed over 15,000 manuscripts and abstracts which were screened, resulting in 202 manuscripts that were ultimately used. In the area of genetics the DNA polymorphisms rs2228480 at the ESR1 gene, rs12589592 at the FBLN5 gene, rs1036819 at the PGR gene and rs1800215 at the COL1A1 gene are significantly associated to POP. In the area of pregnancy, labor and delivery, the analysis confirmed a strong etiologic link between vaginal birth and symptoms of POP, with the first vaginal delivery (OR: 2.65; 95% CI: 1.81-3.88) and forceps delivery (OR: 2.51; 95% CI: 1.24-3.83) being the main determinants. Regarding age and menopause, only age was identified as a risk factor (OR : 1.102; 95% CI: 1.02-1.19) but current data do not identify postmenopausal status as being statistically associated with POP. In several animal models, there are measurable effects of pregnancy, delivery and iatrogenic menopause on the structure/function of vaginal support components, though not on the development of POP. CONCLUSIONS: Genetics, vaginal birth and age all have a strong etiologic link to the development of POP, to which other factors may add or protect against the risk.

Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: Family and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations. METHODS: Updating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria. RESULTS: We screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the ESR1 gene (OR 0.67 95% CI 0.46-0.98, I2 = 0.0%, Venice rating BAB), rs12589592 at the FBLN5 gene (OR 1.46 95% CI 1.11-1.82, I2 = 36.3%, Venice rating BBB), rs484389 in the PGR gene (OR 0.61 95% CI 0.39-0.96, I2 = 32.4%, Venice rating CBB), and rs1800012 at the COL1A1 gene (OR 0.80 95% CI 0.66-0.96, I2 = 0.0%, Venice rating BAB). Further credible novel variants have also been recently identified in genome-wide association studies. CONCLUSION: The genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice.