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Objective: To compile and evaluate the heritability and inheritance patterns of lower urinary tract symptoms (LUTS) in adult cohorts., Methods: Searches of five databases (PubMed, Embase, APA PsycInfo, Global Health, and OVID Medline) commenced on 6 July 2024, resulting in 736 articles retrieved after deduplication. Studies evaluating heritability patterns, gene frequencies, and familial aggregation of symptoms were included for review. Screening and predefined eligibility criteria produced 34 studies for final review. A descriptive analysis of synthesised data was performed, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Cochrane Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool and the Johanna Briggs Institute checklist were used to evaluate these studies., Results: Ten of the 34 studies (29%) described general LUTS, 14 (41%) described symptoms due to benign prostatic enlargement (BPE), nine (26%) described urinary incontinence (UI; urge UI [UUI], stress UI [SUI] and mixed UI [MUI]), four (12%) described nocturia alone, two (6%) described overactive bladder (OAB), and four (13%) described other specific symptoms (frequency, postvoid residual urine volume). BPE symptoms, UI (MUI and UUI), nocturia alone, and frequency alone were associated with genetic predisposition, whilst OAB and SUI had more modest inheritance., Conclusion: The pathogenetic and pharmacological mechanisms fundamental to LUTS manifestation are highly heterogeneous. Further work is required to evaluate the inheritance patterns of LUTS more extensively., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Lower urinary tract dysfunction (LUTD) can manifest as a spectrum of voiding symptoms in childhood, including urinary urgency, frequency, hesitancy, and incontinence. In severe cases, it can lead to frequent urinary tract infections, hydronephrosis, kidney scarring, and chronic kidney disease. Non-neurogenic neurogenic bladder (NNNB) is a diagnosis of exclusion in which children develop discoordination between the detrusor smooth muscle and external urethral sphincter in the absence of neurological or obstructive lesions, resulting in severe LUTD. Historically, such disorders of voiding were thought to result from behavioral maladaptation. However, it is now increasingly recognized that some individuals may have an underlying genetic etiology for their symptoms. Here, we performed exome sequencing for five probands with NNNB or other forms of severe LUTD, and we identified two individuals with monogenic etiologies for their symptoms. One individual had a homozygous exon 9 deletion in HPSE2 and another had a homozygous single amino acid deletion (p.Gly167del) in ARL6. We performed PCR experiments to identify the breakpoints of the HPSE2 exon 9 deletion and implicate microhomology-mediated end joining as a potential mechanism by which the deletion arose. These findings suggest that genetic testing should be considered for children with severe LUTD., (© 2024 Wiley Periodicals LLC.)

Background: The clinical observations suggest a correlation between lower urinary tract symptoms (LUTSs) and mental health problems. Nonetheless, establishing a direct causal relationship between them remains challenging., Methods: We initially conducted a cross-sectional study using 2005-2018 the National Health and Nutrition Examination Survey (NHANES) data. Multivariable-adjusted logistic regression was the primary statistical approach. Additionally, we employed Mendelian randomization (MR) to reducing confounding and reverse causation. Genetic instruments were obtained from publicly available genome-wide association study (GWAS) databases. Inverse Variance Weighted was the primary statistical method., Results: The cross-sectional study involved 29,439 participants. Individuals with mental health problems had a higher risk of urinary incontinence (OR:4.38; 95%CI:3.32-5.76; P < 0.01) and overactive bladder (OR:2.31; 95%CI:2.02-2.63; P < 0.01). MR analysis then indicated a potential causal relationship between mental health problems and LUTSs. Depression symptoms was linked with urinary tract infection (UTI) (OR:1.005; 95%CI:1.003-1.008; P FDR  < 0.01). Anxiety symptoms was related to the occurrence of UTI (OR:1.024; 95%CI:1.011-1.037; P FDR  < 0.01) and bladder calcified/ contracted/ overactive (OR:1.017; 95%CI:1.007-1.027; P FDR  < 0.01). The personality trait of neuroticism was related to the occurrence of cystitis (OR:1.072; 95%CI:1.022-1.125; P FDR  = 0.02), extravasation of urine and difficulties with micturition (OR:1.001; 95%CI:1.001-1.002; P FDR  < 0.01), and urinary frequency and incontinence (OR: 1.001; 95%CI:1.000-1.001; P FDR  < 0.01)., Conclusions: Our study provides various evidence for the correlation between mental health and LUTSs, emphasizing the significance of adopting a holistic approach to LUTSs management that incorporates both physical and psychological factors., Competing Interests: Declaration of competing interest All the authors have declared that no conflicts of interest exist., (Copyright © 2023. Published by Elsevier Inc.)

Multiple sclerosis (MS) often leads to the development of neurogenic lower urinary tract symptoms (LUTS). We previously characterized neurogenic bladder dysfunction in a mouse model of MS induced by a coronavirus, mouse hepatitis virus (MHV). The aim of the study was to identify genes and pathways linking neuroinflammation in the central nervous system with urinary bladder (UB) dysfunction to enhance our understanding of the mechanisms underlying LUTS in demyelinating diseases. Adult C57BL/6 male mice (N = 12) received either an intracranial injection of MHV (coronavirus-induced encephalomyelitis, CIE group), or sterile saline (control group). Spinal cord (SC) and urinary bladders (UB) were collected from CIE mice at 1 wk and 4 wks, followed by RNA isolation and NanoString nCounter Neuroinflammation assay. Transcriptome analysis of SC identified a significantly changed expression of >150 genes in CIE mice known to regulate astrocyte, microglia and oligodendrocyte functions, neuroinflammation and immune responses. Two genes were significantly upregulated (Ttr and Ms4a4a), and two were downregulated (Asb2 and Myct1) only in the UB of CIE mice. Siglec1 and Zbp1 were the only genes significantly upregulated in both tissues, suggesting a common transcriptomic link between neuroinflammation in the CNS and neurogenic changes in the UB of CIE mice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Clarkson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To clarify the role of Trp64Arg polymorphisms of the gene encoding the β 3 -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 β 3 -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 β 3 -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 β 3 -adrenoceptor gene polymorphisms on the genitourinary organs might be weak, whether men possess the Trp64Arg variant of the β 3 -adrenoceptor gene might not critically affect urinary quality of life, but modestly affect the lower urinary tract function., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Inflammation-related prostate fibrosis (PF) is strongly associated with impaired urethral function and lower urinary tract symptoms (LUTS) severity. The aim of this study was to investigate the effects of RSV in patients with small prostate volume and LUTS. Sixty-four patients with PF were randomized either to RSV therapy (group A= 32 patients) or placebo (group B= 32 patients). At baseline (T0) and after 2-months (T2), patients of both groups underwent administration of NIH-Chronic Prostatic Symptom Index (NIH-CPSI) and International Prostate Symptom Score (IPSS) questionnaires for prostatitis and LUTS, respectively, and Expressed Prostatic Secretion (EPS) assays. After two months, only, group A patients treated with RSV showed significant symptomatic improvement of all NIH-CPSI and IPSS subscale scores, as well as a better EPS assay after prostate massage, in terms of high amount of prostatic volume and reduced white blood cells counts. Our data suggested pharmacological advantage after 2-month treatment with RSV in selected patients with PF for the treatment of voiding and storage complaints., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Benign prostate hyperplasia (BPH) is the most common disease among aging males, but no reports have addressed the prevalence of BPH in Zhengzhou. Therefore, we aimed to understand the prevalence of BPH in men aged 40 years or older in Zhengzhou's rural areas through a cross-sectional study and analyzed the correlation with epidemiologic factors and the heritability of the disease., Materials and Methods: A multistage sampling method was used to randomly select male respondents in Zhengzhou's rural areas. Men who were 40 years of age or older and their first-degree relatives were subjected to the International Prostate Symptom Score (IPSS) and related examinations. Heritability was calculated according to the prevalence of the first-degree relatives in the case and control groups., Results: The prevalence of BPH was 10.04%. Its prevalence increased with age, from 2.17% in men aged 40-44 years to 31.11% in men aged 80 years or older. The average volume of the prostate was 17.16 ± 7.96 mL, and the average IPSS was 5.89 ± 5.91. The analysis of the correlation between the associated risk factors and BPH revealed that prostatitis and a history of prostatic hyperplasia were significant factors. Obesity, smoking, drinking, diabetes, and hypertension were not correlated with BPH. Of the 94 first-degree relatives of the cases, 53 had BPH (56.38%); of the 106 first-degree relatives of the controls, five had BPH (4.72%). Heritability appeared to account for 40.48% of BPH cases. The heritability of incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia was 43.28, 71.37, 9.67, 5.67, 2.70, 53.36, and 19.12%, respectively., Conclusion: The total prevalence of BPH in men aged 40 years or older in Zhengzhou's rural areas was 10.04%, and the heritability of prostatic hyperplasia was 40.48%., (© 2018 Wiley Periodicals, Inc.)

Aims: Mechanosensitivity of the urinary bladder is regulated by many factors including mechano-gated two-pore domain (K 2 P, KCNK) potassium channels. TWIK-related K + channel, TREK-1, is a predominantly expressed member of K 2 P channel family in the human detrusor, and its expression and function are diminished in patients with overactive lower urinary tract symptoms (LUTS). The changes in channel activity may result from spontaneously occurring gene mutations. The aim of this study was to compare single nucleotide polymorphisms (SNPs) in TREK-1 channel between patients with LUTS and healthy donors., Methods: Six SNPs (rs370266806, rs373919966, rs758937019, rs769301539, rs772497750, and rs775158737) in two pore domains of human TREK-1 gene were analyzed using TaqMan SNP genotyping assay with manufacturer-designed primers and allele-specific probes. The screening was done in control bladders and detrusor specimens from patients with overactive LUTS. Statistical analyses were performed using R, Fisher's exact test and Hardy-Weinberg Equilibrium., Results: Six SNPs in two pore domains of the human TREK-1 gene were analyzed in human bladder specimens. The frequencies of rs758937019-CT genotype (P = 0.0016) and rs758937019-T allele (P = 0.0022) were significantly higher in the group with overactive LUTS. There was no significant association of rs775158737-GA genotype and rs775158737-A allele with the overactive LUTS, though they were present only in the overactive LUTS group., Conclusions: Our results provide evidence that altered expression and function of TREK-1 channel in patients with overactive LUTS could be due to genetic polymorphisms in the pore domains of TREK-1 channel (rs758937019)., (© 2018 Wiley Periodicals, Inc.)

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r g  = 0.77 (P = 2.6 × 10 -11 ), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10 -55 ). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.

Aims: To explore whether autophagy plays a role in the remodeling of bladder smooth muscle cells (SMCs) in children with neurogenic lower urinary tract dysfunction (NLUTD), we investigated the effect of autophagy in NLUTD in the paediatric population., Methods: Bladder biopsies were taken from children with NLUTD and healthy donors as controls. Samples were labeled with the SMC markers calponin, smoothelin, and the autophagy proteins LC3, ATG5, and Beclin1. The contractile ability of bladder derived SMCs was investigated., Results: ATG5 gene and protein was upregulated in NLUTD muscle tissue compared to normal bladder. NLUTD muscle exhibited a punctated immunostaining pattern for LC3 in a subset of the SMCs, confirming the accumulation of autophagosomes. Pronounced elevation of ATG5 in the SMC in NLUTD tissue was associated with a downregulation of the key contractile proteins smoothelin and calponin. Pharmacological blocking of autophagy completely stopped the cells growth in normal bladder SMCs. Inhibition of autophagy in the NLUTD SMCs, with already elevated levels of ATG5, resulted in a reduction of ATG5 protein expression to the basal level found in normal controls., Conclusions: Our study suggests that autophagy is an important factor affecting the remodeling of SMCs and the alteration of functionality in bladder smooth muscle tissue in the NLUTD. Since autophagy can be influenced by oral medication, this finding might lead to novel strategies preventing the deterioration of NLUTD muscle., (© 2018 Wiley Periodicals, Inc.)

Objective: To analyze lower urinary tract symptoms and benign prostate hyperplasia features among male BRCA1 and 2 carriers and an age-matched control group., Methods: Male BRCA carriers and noncarriers aged 40-70 years were enrolled in our cross-sectional study. Relevant clinical data were collected, and patients filled the International Prostate Symptom Score. Patients also underwent prostate-specific antigen (PSA) blood testing, digital rectal examination, uroflowmetry, and post-void residual ultrasound examination. As part of their routine follow-up, BRCA carriers underwent prostate magnetic resonance imaging., Results: Overall, 87 carriers and 30 noncarriers were enrolled. The median age, mean body mass index, and comorbidities in both groups were similar. Maximal flow (QMAX) was higher in the noncarrier group (16.9 mL/s vs 12 mL/s, P = .01). Mean prostate volume among all BRCA carriers was 38.8 cc (19.7), but BRCA1 patients had larger glands with higher mean PSA and PSA density than BRCA2 patients (41.8 cc vs 33.1 cc, P = .047, 1.84 ng/mL vs 1.07 ng/mL, P = .006, and .044 vs .032, P = .042, respectively). Multivariate analysis demonstrated age being the sole significant predictor of PSA density in BRCA2 patients., Conclusion: Male carrying BRCA mutations have significantly lower QMAX than healthy men. BRCA1 patients have on average larger prostate glands and higher PSA than BRCA2 patients. Further research is required to decipher the association of lower urinary tract symptoms or benign prostate hyperplasia with BRCA carriers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome-wide evaluation of inherited risks and possible mechanisms of etiology in BPH., Methods: We performed a three-stage, genome-wide association study (GWAS) of men from three independent populations, the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, the CLUE II cohort, and a Finnish hospital-based population. DNA samples were genotyped using the Illumina HumanOmniExpress BeadChip in REDUCE and CLUE II, and using the Sequenom iPLEX system for the confirmation stage in the Finnish population. A logistic regression model was used to evaluate the association between each SNP and BPH/LUTS., Results: Fourteen SNPs reached P < 5.0 × 10 -4 in the meta-analysis of the two GWASs (CLUE II and REDUCE). A total of 773 SNPs were chosen for the confirmation step in the Finish cohort. Only one SNP (rs17144046) located ∼489 kb downstream of GATA3 remained significant after correction for multiple testing (P < 6.5 × 10 -5 ). This SNP marginally reached the GWAS significance level after performing a meta-analysis of the three stages (P -meta  = 8.89 × 10 -7 ). Expression quantitative trait loci (eQTL) analyses showed that the risk allele (G) of rs17144046 was significantly associated with increased expression of GATA3 (P = 0.017). Reported studies indicated a close correlation between GATA3 and BPH pathogenesis and progression., Conclusions: Rs17144046 located near GATA3 was significantly associated with BPH/LUTS in three independent populations, but did not reach a stringent GWAS significance level. Genetic variants of GATA3 may play a role in the inherited susceptibility and etiology of BPH/LUTS. Further research in this area is needed., (© 2017 Wiley Periodicals, Inc.)

Introduction: Lower urinary tract symptoms (LUTS) are frequent in motor neuron disease (MND) patients, but clinical factors related to them are unknown. We describe differences in LUTS among MND phenotypes and their relationship with other clinical characteristics, including prognosis., Methods: For this study, we collected clinical data of a previously published cohort of patients diagnosed with classical amyotrophic lateral sclerosis (cALS), progressive muscular atrophy (PMA) or primary lateral sclerosis (PLS) with and without LUTS. Familial history was recorded and the C9ORF72 expansion was analysed in the entire cohort. Patients were followed-up for survival until August 2016., Results: Fifty-five ALS patients (37 cALS, 10 PMA and 8 PLS) were recruited. Twenty-four reported LUTS and neurogenic bladder (NB) could be demonstrated in nine of them. LUTS were not influenced by age, phenotype, disability, cognitive or behavioural impairment, or disease progression, but female sex appeared to be a protective factor (OR=0.39, p=0.06). Neither family history nor the C9ORF72 expansion was linked to LUTS or NB. In the multivariate analysis, patients reporting LUTS early in the disease course tended to show poorer survival., Conclusions: In this study, LUTS appear to be more frequent in male MND patients, but are not related to age, clinical or genetic characteristics. When reported early, LUTS could be a sign of rapid disease spread and poor prognosis. Further prospective longitudinal and neuroimaging studies are warranted to confirm this hypothesis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Symptoms of urinary irritation, urgency, frequency and obstruction, known as lower urinary tract symptoms, are common in urological practice. However, little is known about the etiology or pathogenesis of lower urinary tract symptoms, especially the relative contributions of genetic and environmental factors to the development of these symptoms. We used a classic twin study design to examine the relative contributions of genetic and environmental factors to the occurrence of lower urinary tract symptoms in middle-aged men., Materials and Methods: Twins were members of the Vietnam Era Twin Registry. We used a mail survey to collect data on lower urinary tract symptoms using the I-PSS (International Prostate Symptom Score) instrument. Twin correlations and biometric modeling were used to determine the relative genetic and environmental contributions to variance in I-PSS total score and individual items., Results: Participants were 1,002 monozygotic and 580 dizygotic middle-aged male twin pairs (mean age 50.2 years, SD 3.0). Nearly 25% of the sample had an I-PSS greater than 8, indicating at least moderate lower urinary tract symptoms. The heritability of the total I-PSS was 37% (95% CI 32-42). Heritability estimates ranged from 21% for nocturia to 40% for straining, with moderate heritability (34% to 36%) for urinary frequency and urgency., Conclusions: Genetic factors provide a moderate contribution (20% to 40%) to lower urinary tract symptoms in middle-aged men, suggesting that environmental factors may also contribute substantially to lower urinary tract symptoms. Future research is needed to define specific genetic and environmental mechanisms that underlie the development of these symptoms and conditions associated with lower urinary tract symptoms., Competing Interests: None of the authors have any conflicts of interest to declare., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To prospectively investigate the association of endothelial nitric oxide synthase (eNOS) G894T gene polymorphism with responsiveness to a selective α1 -blocker in men with benign prostatic hyperplasia related lower urinary tract symptoms (BPH/LUTS), as nitric oxide has recently gained increasing recognition as an important neurotransmitter of functions in the lower urinary tract., Patients and Methods: In all, 136 men with BPH/LUTS were recruited from urology outpatient clinics in a university hospital. Oral therapy with doxazosin gastrointestinal therapeutic system (GITS) 4 mg once-daily was given for 12 weeks. The drug efficacy was assessed by the changes from baseline in the total International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ) and post-void residual urine volume (PVR) at 12 weeks of treatment. The 'responders' to doxazosin GITS were defined as those who had a total IPSS decrease of >4 points from baseline. eNOS G894T polymorphism was determined using the polymerase chain reaction-restriction fragment length polymorphism method., Results: Patients had statistically significant improvements in total IPSS, quality of life score, and Qmax (P < 0.01) after a 12-week period of treatment. Using multiple logistic regression analysis adjusted for age and IPSS, our results showed that being a eNOS 894T allele carrier was an independent risk factor for being a drug non-responder (P = 0.03, odds ratio 4.19). Moreover, a decreased responder rate (P = 0.01), as well as the lower improvements in IPSS (P = 0.02) and Qmax (P = 0.03) were significantly associated with increment in the T allele number., Conclusions: The presence of the eNOS 894T allele had a significantly negative impact on responsiveness to a selective α1 -blocker in BPH/LUTS treatment, suggesting that eNOS G894T gene polymorphism may be a genetic susceptibility factor for α1 -blocker efficacy in men with BPH/LUTS., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Benign prostatic hyperplasia, prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction. To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1(+/-);Pten(fl/+) mice, which are genetically predisposed to prostate neoplasia, were exposedin uteroand during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 μg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17 β-estradiol (2.5 mg) and testosterone (25 mg) (T+E2) via slow release subcutaneous implants.In uteroand lactational (IUL) TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse LUT anatomy or function. By comparison, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution. We propose a 2-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The aim of this study was to determine the relationship between polymorphisms in the IL-28B and IL-28R genes and lower urinary tract symptoms (LUTS) in Chinese patients. Genomic DNA was extracted from 553 whole blood samples from 233 patients with LUTS resulted from benign prostatic hyperplasia and 320 control subjects. The IL-28B rs12979860 and rs8099917, and IL-28Rα rs10903035 and rs11249006 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. For rs10903035, the frequencies of the "G" allele and the "AG/GG" genotypes in the LUTS group were significantly lower than those in the control group ("G" vs "A": OR = 0.655, 95%CI = 0.506-0.849; AG/GG vs "AA": OR = 0.538, 95%CI = 0.379-0.764, respectively). Combined effects analysis of rs12979860 and rs10903035 showed that the "CC+AG/GG" and "CT+AA" genotypes were significantly less frequent in the LUTS group ("CC+AG/GG" vs "CC+AA": OR = 0.553, 95%CI = 0.381-0.801; "CT+AG/GG" vs "CC+AA": OR = 0.429, 95%CI = 0.198- 0.927, respectively). In addition, the combined effects of the rs8099917 and rs10903035 "TT+AG/GG" and "GT+AG/GG" genotypes were also significantly lower in the LUTS group ("TT+AG/GG" vs "TT+AA": OR = 0.569, 95%CI = 0.395-0.821; "GT+AG/GG" vs "TT+AA": OR = 0.318, 95%CI = 0.128-0.788, respectively). Stratification analysis revealed that the frequencies of the rs11249006 "AG/GG" genotypes in the subgroups of size ≤4.11 and IPSS ≤ 28 were significantly higher than those in the subgroups of size >4.11 and IPSS > 28. Therefore, the IL-28Rαgene polymorphism might be involved in the development of LUTS.

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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Urofacial syndrome (UFS) is characterised by congenital bladder dysfunction accompanied by a characteristic abnormal grimace upon smiling and crying. In recent years, biallelic mutations of HPSE2 and LRIG2 have been reported in UFS patients. Non-neurogenic neurogenic bladder (NNNB) has a bladder identical to UFS without typical facial features. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression., Methods: Patients with UFS, NNNB and severe LUTD were enrolled in the study. We examined a total of 35 patients from 33 families. There were seven UFS patients from five different families, 21 patients with NNNB and seven with LUTD. HPSE2 gene mutation analysis was performed using the polymerase chain reaction protocol followed by Sanger sequencing in these patients., Results: A twin pair with UFS was found to be homozygous for c.457C>T (p.Arg153*) mutation. No other pathogenetic variant was detected., Conclusion: HPSE2 mutations were found in one UFS family but not detected in patients with NNNB and severe LUTD. Considering the increasingly recognised cases of NNNB that were diagnosed in early childhood period, genetic factors appear to be responsible. Thus, further genetic studies are needed to discover novel associated gene variants in these bladder anomalies., (© 2015 S. Karger AG, Basel.)

Context: Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS., Objective: To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations., Evidence Acquisition: A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies., Evidence Synthesis: We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes., Conclusions: Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses., Patient Summary: Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Lower urinary tract (LUT) symptoms become prevalent with aging and affect millions; however, therapy is often ineffective because the etiology is unknown. Existing assays of LUT function in animal models are often invasive; however, a noninvasive assay is required to study symptom progression and determine genetic correlates. Here, we present a spontaneous voiding assay that is simple, reproducible, quantitative, and noninvasive. Young female mice from eight inbred mouse strains (129S1/SvImJ, A/J, C57BL/6J, NOD/ShiLtJ, NZO/H1LtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) were tested for urination patterns on filter paper. Repeat testing at different times of the day showed minimal within-individual and within-strain variations, but all parameters (spot number, total volume, percent area in primary void, corner voiding, and center voiding) exhibited significant variations between strains. Calculation of the intraclass correlation coefficient, an estimate of broad-sense heritability, for each time of day and for each voiding parameter revealed highly significant heritability [spot number: 61%, percent urine in primary void: 90%, and total volume: 94% (afternoon data)]. Cystometrograms confirmed strong strain-specific urodynamic characteristics. Behavior-voiding correlation analysis showed no correlation with anxiety phenotypes. Diagnostically, the assay revealed LUT symptoms in several systems, including a demonstration of voiding abnormalities in older C57BL/6J mice (18-24 mo), in a model of protamine sulfate-induced urothelial damage and in a model of sucrose-induced diuresis. This assay may be used to derive pathophysiological LUT readouts from mouse models. Voiding characteristics are heritable traits, opening the way for genetic studies of LUT symptoms using outbred mouse populations., (Copyright © 2014 the American Physiological Society.)

Background: Approximately one-third of patients fail medical treatment for benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) requiring surgical intervention. Our purpose was to establish a molecular characterization for patients undergoing surgical intervention for LUTS to address therapeutic deficiencies., Methods: Clinical, molecular, and histopathological profiles were analyzed in 26 patients undergoing surgery for severe LUTS. Incidental transitional zone nodules were isolated from 37 patients with mild symptoms undergoing radical prostatectomy. Clinical parameters including age, prostate volume, medication, prostate specific antigen, symptom score, body mass index, and incidence of diabetes were collected. Multivariate logistic regression analysis with adjustments for potential confounding variables was used to examine associations between patient clinical characteristics and molecular targets identified through molecular profiling., Results: Compared to incidental BPH, progressive symptomatic BPH was associated with increased expression of the activating protein-1 transcription factor/chemokine network. As expected, inverse correlations were drawn between androgen receptor levels and age, as well as between 5α-reductase inhibitor (5ARI) treatment and tissue prostate specific antigen levels; however, a novel association was also drawn between 5ARI treatment and increased c-FOS expression., Conclusions: This study provides molecular evidence that a network of pro-inflammatory activating protein-1 transcription factors and associated chemokines are highly enriched in symptomatic prostate disease, a profile that molecularly categorizes with many other chronic autoimmune diseases. Because 5ARI treatment was associated with increased c-FOS expression, future studies should explore whether increased activating protein-1 proteins are causal factors in the development of symptomatic prostate disease, inflammation or resistance to traditional hormonal therapy., (© 2014 Wiley Periodicals, Inc.)

Aims: As the presence of a Trp64Arg polymorphism of the gene encoding the β(3)-adrenoceptor (B3AR) has been linked to the presence of overactive bladder, we investigated whether additional polymorphisms are detectable in this gene and explore their relationships parameters related to lower urinary tract function., Methods: The coding region and adjacent stretches of the B3AR gene was sequenced in 91 patients. In total, 1015 patients from a single academic hospital were genotyped for the presence of two single nucleotide polymorphisms. Symptom scores and parameters from pressure-flow studies were analyzed relative to genotype in the B3AR gene., Results: No frequent novel polymorphisms were detected in the coding region. Five polymorphisms were found in the non-coding region of the gene but were in complete linkage with the 64Arg allele. Out of 32 parameters including bladder compliance, only prostate size was weakly (44 vs. 39 mL) but significantly associated with the 64Arg allele, but was not mirrored by an association with prostate-specific antigen levels., Conclusions: Our data do not support the hypothesis that polymorphisms in the B3AR gene are associated with alterations of bladder function., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: While a clear heritable component underlies lower urinary tract symptoms and benign prostatic hyperplasia, few studies have identified specific genetic factors. In contrast, recent genome-wide association studies identified single nucleotide polymorphisms that increase prostate cancer risk. Some of these single nucleotide polymorphisms may also predispose to surgical intervention for benign prostatic hyperplasia. We determined whether these single nucleotide polymorphisms are also associated with lower urinary tract symptom severity and benign prostatic hyperplasia medication use., Materials and Methods: The genotypes of 38 single nucleotide polymorphisms previously associated with prostate cancer risk were determined for 1,168 healthy white male volunteers. American Urological Association symptom index score and medication for benign prostatic hyperplasia were documented prospectively. Statistical analyses were done to compare the frequency of the single nucleotide polymorphisms with American Urological Association symptom index and benign prostatic hyperplasia medication use., Results: Several single nucleotide polymorphisms, including rs2736098 on chromosome 5p15, showed a significant relationship with benign prostatic hyperplasia medication. After adjusting for the other genetic variants, patient age and medication use, rs1571801 on chromosome 9q33.2 (OR 1.31, 95% CI 1.0-1.74) and rs5945572 on chromosome Xp11 (OR 1.28, 95% CI 1.04-1.59) were significantly associated with increased urinary symptoms. In contrast, rs445114 on chromosome 8q24 was marginally associated with decreased urinary symptoms (OR 0.83, 95% CI 0.66-1.01)., Conclusions: Of 38 single nucleotide polymorphisms that predispose to prostate cancer we identified 3 that are also associated with a well characterized lower urinary tract symptom phenotype. These single nucleotide polymorphisms may aid in the improved characterization of men with lower urinary tract symptoms/benign prostatic hyperplasia., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Lower urinary tract dysfunction is highly prevalent, but has relatively low persistence and compliance with therapy because of poor efficacy. Although urodynamic study is the gold standard for detailed evaluation of lower urinary tract dysfunction, urodynamic study has limitations as a biomarker, such as invasiveness and a lack of reproducibility of symptoms. Thus, many investigations about new biomarkers for lower urinary tract dysfunction have been carried out and reported. For imaging biomarkers, bladder and prostate parameters assessed by ultrasonography have been used to evaluate lower urinary tract dysfunction. For urinary biomarkers, neurotrophins, such as nerve growth factor and brain derived neurotrophics factor, prostaglandins and cytokines, have been analyzed and evaluated. Among these, nerve growth factor is considered one of the key factors in the pathophysiology of lower urinary tract dysfunction, and is researched in various ways. Serum markers have suggested that C-reactive protein and sex hormones have a relationship with lower urinary tract dysfunction. The possibility of genetic biomarkers in lower urinary tract dysfunction has also been raised. Nevertheless, as yet these biomarkers have not shown enough evidence to reflect lower urinary tract dysfunction and require further investigation. This review will discuss promising and potential biomarkers in lower urinary tract dysfunction to date., (© 2012 The Japanese Urological Association.)

Recent studies from our group suggest that extracellular matrix (ECM) deposition and fibrosis characterize the peri-urethral prostate tissues of some men suffering from Lower Urinary Tract Symptoms (LUTS) and that fibrosis may be a contributing factor to the etiology of LUTS. Fibrosis can generally be regarded as an errant wound-healing process in response to chronic inflammation, and several studies have shown that the aging prostate tissue microenvironment is rich with inflammatory cells and proteins. However, it is unclear whether these same inflammatory proteins, particularly CXC-type chemokines, can mediate myofibroblast phenoconversion and the ECM deposition necessary for the development of prostatic tissue fibrosis. To examine this, immortalized and primary prostate stromal fibroblasts treated with TGF-β1, CXCL5, CXCL8, or CXCL12 were evaluated morphologically by microscopy, by immunofluorescence and qRT-PCR for αSMA, collagen 1, vimentin, calponin, and tenascin protein and transcript expression, and by gel contraction assays for functional myofibroblast phenoconversion. The results of these studies showed that that immortalized and primary prostate stromal fibroblasts are induced to express collagen 1 and 3 and αSMA gene transcripts and proteins and to undergo complete and functional myofibroblast phenoconversion in response to CXC-type chemokines, even in the absence of exogenous TGF-β1. Moreover, CXCL12-mediated myofibroblast phenoconversion can be completely abrogated by inhibition of the CXCL12 receptor, CXCR4. These findings suggest that CXC-type chemokines, which comprise inflammatory proteins known to be highly expressed in the aging prostate, can efficiently and completely mediate myofibroblast phenoconversion and may thereby promote fibrotic changes in prostate tissue architecture associated with the development and progression of male lower urinary tract dysfunction.