Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

PURPOSE: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. MATERIALS AND METHODS: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction. RESULTS: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). CONCLUSIONS: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.

Ultrasound technique for the assessment of urethral descent assessment technique (UDAT) in healthy volunteers.

Bladder neck descent (BND) has been implicated in the pathophysiology of stress incontinence and prolapse. The aim of this study was to evaluate a novel 2D technique for the evaluation of BND, the Urethral Descent Assessment Technique (UDAT). UDAT involves measuring BND during dynamic manoeuvres in live 2D ultrasound, by using the geometrical properties of parallel lines. The internal urethral meatus and distal end of the urethra are used as reference points. Y1 is the urethral height at rest (also the urethral length when the urethra is straight). Y2 is the urethral height on Valsalva. Y1 and Y2 are parallel lines. Y1-Y2 = BND. A horizontal line (X) connecting Y1 and Y2 is the forward movement of the bladder neck.Y1 mean 30.4 mm (95% CI ± 1.36 mm). Y2 mean 24.2 mm (95% CI ± 2.58 mm). X mean 12.1 mm (95% CI ± 1.66 mm). BND mean 6.2 mm (95% CI ± 1.47 mm). Bland-Altman plots and linear regression showed that UDAT is repeatable and reliable.Impact statementWhat is already known on this subject? Bladder neck descent (BND) has been associated with stress incontinence and prolapse nearly a century. In 1975, Green introduced a classification based on X-ray cysto-urethrograms. Between 1989 and 1995, a 2D technique was described that had several limitations.What do the results of this study add? This study validates a novel technique for the assessment of bladder neck descent using 2D ultrasound and provides a reference range of BND for normal nulliparous women.What are the implications of these findings for clinical practice and/or further research? This is a simple and quick technique that could be adopted in research and clinical practice in the future to assess stress incontinence and anterior compartment prolapse.

Associations between individual lower urinary tract symptoms and bacteriuria in random urine samples in women.

AIMS: Previous studies have noted an association between a diagnosis of overactive bladder and bacteriuria, but little is understood about the relationship of bacteriuria to specific LUTS. We hypothesized that bacteriuria in women would be associated with increased self-reported symptom scores for a wide range of LUTS. METHODS: Women were recruited from general gynecology and urogynecology outpatient clinics in a secondary care setting. Women completed the 12-item International Consultation on Incontinence Questionnaire for Female Lower Urinary Tract Symptoms and provided a clean-catch mid-stream specimen of urine for microscopy and culture. Women with acute urinary tract infection were excluded. Three statistical approaches (Mann-Whitney U-test, multivariable logistic regression, and receiver operating characteristic curves) were used to assess differences in symptom scores between women with and without bacteriuria. RESULTS: Two hundred forty-seven women were recruited, aged 22-82. Sixteen of 247 urine samples (6.5%) demonstrated significant bacteriuria, growing a different range of organisms. Women with significant bacteriuria were more likely to have nocturia (OR 3.56, 95% CI 1.19-10.6, P = 0.02), urgency (OR 6.66, 95% CI 1.47-30.06, P = 0.01), bladder pain (OR 2.82, 95% CI 1-7.92, P = 0.049), urgency incontinence (OR 2.92, 95% CI 1.02-8.36, P = 0.046), nocturnal enuresis (OR 4.21, 95% CI 1.32-13.41, P = 0.01). After adjustment for age, parity, symptomatic prolapse, menopausal status and history of mid-urethral sling urinary urgency, bladder pain, nocturia, and nocturnal enuresis remained significantly associated. CONCLUSIONS: Bacteriuria is associated with a range of LUTS including nocturia, urgency, and bladder pain supporting a role for bacterial colonization in the pathogenesis of OAB symptoms.

Apolipoprotein(a) acts as a chemorepellent to human vascular smooth muscle cells via integrin αVß3 and RhoA/ROCK-mediated mechanisms.

Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease. Vascular smooth muscle cell (SMC) motility and plasticity, functions that are influenced by environmental cues, are vital to adaptation and remodelling in vascular physiology and pathophysiology. Lp(a) is reportedly damaging to SMC function via unknown molecular mechanisms. Apolipoprotein(a) (apo(a)), a unique glycoprotein moiety of Lp(a), has been demonstrated as its active component. The aims of this study were to determine functional effects of recombinant apo(a) on human vascular SMC motility and explore the underlying mechanism(s). Exposure of SMC to apo(a) in migration assays induced a potent, concentration-dependent chemorepulsion that was RhoA and integrin αVß3-dependent, but transforming growth factor ß-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre-treatment, αVß3 neutralising antibody and tyrosine kinase inhibition all markedly inhibited apo(a)-mediated SMC migration. Our data reveal unique and potent activities of apo(a) that may negatively influence SMC remodelling in cardiovascular disease. Circulating levels of Lp(a) are resistant to lipid-lowering strategies and hence a greater understanding of the mechanisms underlying its functional effects on SMC may provide alternative therapeutic targets.