The effect of ß3-adrenoceptor gene polymorphisms on lower urinary tract function in males.

PURPOSE: To clarify the role of Trp64Arg polymorphisms of the gene encoding the ß3-adrenoceptor for lower urinary tract function in males, the present study investigated the association between the Trp64Arg polymorphisms and lower urinary tract symptoms (LUTS) and function. METHODS: This prospective observational study included patients who underwent robot-assisted radical prostatectomy. Before surgery, blood samples were collected, and analyses of ß3-adrenoceptor gene polymorphism were performed using the real-time polymerase chain reaction. The present cohort was divided into patients with wild type (Trp64Trp) and with variant type (Trp64Arg + Arg64Arg), and LUTS and lower urinary tract function before surgery were compared between them. RESULTS: Wild type was found in 247 patients, with variant type in 129. There were no significant differences in LUTS between the two groups. Residual urine volume (PVR) (wild type: variant type = 47 ± 53 mL: 58 ± 77 mL, P = 0.04) and voiding time on uroflowmetry (wild type: variant type = 29 ± 15 s: 33 ± 17 s, P = 0.04) were significantly increased in the variant type. CONCLUSION: The Trp64Arg variant of the ß3-adrenoceptor gene significantly increased PVR and voiding time in men. However, it was not significantly associated with the emergence of LUTS. Thus, since the effect of ß3-adrenoceptor gene polymorphisms on the genitourinary organs might be weak, whether men possess the Trp64Arg variant of the ß3-adrenoceptor gene might not critically affect urinary quality of life, but modestly affect the lower urinary tract function.

SMAD2, SMAD3 and TGF-ß GENE expressions in women suffering from urge urinary incontinence and pelvic organ prolapse.

We evaluated the changes in the levels of TGF-ß and SMAD gene and protein expression in the uterosacral ligament (USL) of patients with concomitant pelvic organ prolapse (POP) and urgency urinary incontinence (UUI) to illuminate the pathophysiology of UUI. The TGF-ß pathway is involved in collagen synthesis and degradation. The Transforming Growth Family-ß (TGF-ß) superfamily has essential intracellular signaling components, such as newly identified SMAD family members. We evaluated the changes in the levels of TGF-ß and SMAD gene and protein expression in the USL of patients with concomitant pelvic organ prolapse (POP) and UUI. This study included 10 patients who had been diagnosed with POP and UUI in the study group and 14 asymptomatic women without complaints of POP and UUI in the control group. Biopsy samples were collected from bilateral USL tissues during vaginal or abdominal hysterectomy. Total RNA was extracted from USL tissue and analyzed by qPCR. The protein expression levels were also analyzed with ELISA. In UUI patients, SMAD3 and TGF-ß1 gene expression levels significantly decreased compared to the control patients (p = 0.008 and p = 0.006, respectively). SMAD2 mRNA levels did not differ between the study and control groups (p = 0.139). No differences was found in the levels of SMAD2, SMAD3, and TGF-ß1 protein expression between the two groups. The reduction in the gene and protein expression levels of SMAD3 and TGF-ß1 in women with UUI and lax uterosacral ligaments may indicate a causal link.Clinical trial registration: NCT04525105.

Genetic variants and expression changes in urgency urinary incontinence: A systematic review.

AIM: To perform a systematic review summarizing the knowledge of genetic variants, gene, and protein expression changes in humans and animals associated with urgency urinary incontinence (UUI) and to provide an overview of the known molecular mechanisms related to UUI. METHODS: A systematic search was performed on March 2, 2020, in PubMed, Embase, Web of Science, and the Cochrane library. Retrieved studies were screened for eligibility. The risk of bias was assessed using the ROBINS-I (human) and SYRCLE (animal) tool. Data were presented in a structured manner and in the case of greater than five studies on a homogeneous outcome, a meta-analysis was performed. RESULTS: Altogether, a total of 10,785 records were screened of which 37 studies met the inclusion criteria. Notably, 24/37 studies scored medium-high to high on risk of bias, affecting the value of the included studies. The analysis of 70 unique genes and proteins and three genome-wide association studies showed that specific signal transduction pathways and inflammation are associated with UUI. A meta-analysis on the predictive value of urinary nerve growth factor (NGF) levels showed that increased urinary NGF levels correlate with UUI. CONCLUSION: The collective evidence showed the involvement of two molecular mechanisms (signal transduction and inflammation) and NGF in UUI, enhancing our understanding of the pathophysiology of UUI. Unfortunately, the risk of bias was medium-high to high for most studies and the value of many observations remains unclear. Future studies should focus on elucidating how deficits in the two identified molecular mechanisms contribute to UUI and should avoid bias.

Genetic contributions to urgency urinary incontinence in women.

PURPOSE: We identify genetic variants associated with urgency urinary incontinence in postmenopausal women. MATERIALS AND METHODS: A 2-stage genome-wide association analysis was conducted to identify variants associated with urgency urinary incontinence. The WHI GARNET substudy with 4,894 genotyped post-reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000 Genomes ALL Phase I integrated variant set as a reference. Controls reported no urgency urinary incontinence at enrollment or followup. Cases reported monthly or greater urgency urinary incontinence and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict urgency urinary incontinence case vs control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates. RESULTS: Following quality control, 975,508 single nucleotide polymorphisms in 2,241 cases (discovery 1,102; replication 1,133) and 776 controls (discovery 405, replication 371) remained. Genotype imputation resulted in 9,077,347 single nucleotide polymorphisms and insertions/deletions with minor allele frequency greater than 0.01 available for analysis. Meta-analysis of the discovery and replication samples identified 6 loci on chromosomes 5, 10, 11, 12 and 18 associated with urgency urinary incontinence at p <10(-6). Of the loci 3 were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15 and the CIT gene on chromosome 12q24. The other 3 loci were intergenic. CONCLUSIONS: Although environmental factors also likely contribute, this first exploratory genome-wide association study for urgency urinary incontinence suggests that genetic variants in the ZFP521, CIT and ADAMTS16 genes might account for some of the observed heritability of the condition.

Genetic susceptibility to urinary incontinence: implication of polymorphisms of androgen and oestrogen pathways.

PURPOSE: Although existence of genetic factors predisposing to urinary incontinence in women is widely admitted, precise molecular and genetic variations implicated are still unknown. Given the established influence of steroids metabolism in incontinence, we studied the correlation between polymorphisms of genes of oestrogen/androgen pathways and urinary incontinence in women, in order to raise evidence of genetic susceptibility. METHODS: A case-control study included 121 cases and 66 controls. Age, familial history of incontinence, gynaecologic history and age of menopause were collected. Patients were classified into three groups: control, urge urinary incontinence (UUI), stress urinary incontinence (SUI). Genetic polymorphisms were determined after amplification by PCR for the following genes: CYP-19, CYP17, androgen receptor (AR) and oestrogen receptor (ESR-1). Statistical analysis was performed to study correlation between genotype and presence of a subtype of incontinence. RESULTS: A total of 187 patients were analysed: 66 were controls, 30 presented UUI and 107 presented SUI. Patients presenting incontinence had significantly more often familial history of incontinence than controls. AR polymorphism (combination of 2 alleles containing more than 21 CAG repeats) is significantly associated with UUI (P = 0.02). Polymorphisms of ESR-1, CYP17 and CYP19 were not associated with any subtype of urinary incontinence. CONCLUSIONS: This study shows that AR polymorphism is linked to genetic susceptibility to urinary incontinence. This result suggests that this disease is partly gene-related and encourages larger studies to explore the genetics factors of urinary incontinence.