1. Department of Epidemiology and Biostatistics and Department of Urogynaecology, Imperial College London, London, UK;2. Department of Urology Research, University of Sheffield, Sheffield, UK;3. Department of Urology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland, and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada;4. Beatson Institute for Cancer Research, University of Glasgow, Glasgow, UK;5. Department of Urology, Tampere University Hospital, and School of Medicine, University of Tampere, Tampere, Finland;6. Department of Reproductive Medicine, University of California, San Diego, San Diego, CA, USA, and Department of Obstetrics and Gynecology, Kaiser Permanente, San Diego, CA, USA;g Department of Urogynaecology, King''s College London, London, UK;h University College London Medical School, London, UK;i Clinical Trials Unit, Imperial College London, London, UK;j Institute for Reproductive and Developmental Biology, Imperial College London, London, UK;k Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK;l Section of Genomic Medicine, National Heart and Lung Institute and Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK;m Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA), Centre for Environment and Health, School of Public Health, Imperial College, London, UK, Institute of Health Sciences and Biocentre, Oulu, University of Oulu, Finland, Unit of Primary Care, Oulu University, Hospital, Oulu, Finland and Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland;n Department of Urogynaecology, Imperial College London, London, UK;o Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
Abstract:
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 (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.
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.
