Systematic Review and Meta-analysis of Candidate Gene Association Studies of Lower Urinary Tract Symptoms in Men

Abstract

ContextAlthough 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.ObjectiveTo 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 acquisitionA 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 synthesisWe 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 (I2 = 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.ConclusionsFew 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 summaryCombining 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.

Correlation between prostate volume and single nucleotide polymorphisms implicated in the steroid pathway

“…The latter has been previously studied in many reports, but mainly via a candidate-gene approach. Cartwright et al [15] recently gathered the results of those multiple reports in a systematic review and performed meta-analyses. They concluded that only rs731236 variant of the vitamin D receptor gene was consistently associated with a reduced risk of LUTS in men across different populations.…”

“…However, few studies have been conducted about genetic markers of BPH, and were mainly based on a candidate-gene approach. To date, no genetic variant has been clearly linked to BPH, BPE, or LUTS, except in vitamin D pathway [15]. In addition, a major limitation of previously published data is the lack of correct phenotype definition, the endpoint being loosely BPH, LUTS, prostate volume categories, or BPH treatments.…”

The Epidemiology of Pelvic Floor Disorders and Childbirth

“…22 A meta-analysis provided moderate evidence of the genetic association for urinary symptoms in women, with certain genes having an odds ratio (OR) of 2.5 for OAB and 2.1 for SUI. 23 Although specific genetic predisposition has not been identified, a systematic review of genetic studies found that collagen type 3 alpha 1 was associated with POP (OR 4.79). 24 …”

Responsiveness to medical benign prostatic hyperplasia therapy: is there a genetic factor?

“…None of these studies provided compelling evidence that one of these polymorphisms (or combinations thereof) could serve as a clinically relevant marker [4,5]. As indicated by Cartwright et al [5], many of these genetic studies are hampered by a small sample size, lack of genotyping quality control, inadequate adjustment for populations from heterogeneous descent groups, and poorly defined/inhomogeneous study endpoints.…”

“…Within the past decade numerous polymorphisms in the steroid-metabolism pathway, in cytokine genes, in the vitamin D receptor gene, the a-adrenoceptor gene, in homeobox genes, in the angiotensin converting enzyme, the glutathione S-transferase gene, and in the nitric oxide system (just to mention the most frequently studied ones) have been correlated to several clinical parameters of BPH/LUTS, such as symptom status, prostate volume, maximum urinary flow rate and the natural history of the disease [4,5]. None of these studies provided compelling evidence that one of these polymorphisms (or combinations thereof) could serve as a clinically relevant marker [4,5].…”