An international research effort aimed at identifying the genetic basis of lower urinary tract symptoms (LUTS) has identified five candidate genes, one of which – encoding the vitamin D receptor (VDR) – is consistently protective against these symptoms in men.
LUTS in men is highly heritable but little is known about the specific genetic polymorphisms involved. In this study, Rufus Cartwright (Imperial College London, UK) and colleagues across Europe and North America systematically reviewed the literature in order to identify and further characterise potential candidate genes and polymorphisms.
A total of 74 relevant studies were identified. All used a candidate gene approach, the authors note; no genome-wide association studies have been performed to date. The studies reported polymorphisms in or near 70 different genes. Of these, 35 polymorphisms, in or near 24 genes, were subjected to meta-analysis.
Five polymorphisms from the original pool of 70 were found to be significantly associated with LUTS, report Cartwright et al in European Urology.
These were rs4340 in the angiotensin-converting enzyme (ACE) gene; rs5030739 in the elaC homolog 2 (ELAC2) gene; the null allele in the glutathione S-transferase M1 (GSTM1) gene; the noncoding rs2736098 in the telomerase reverse transcriptase (TERT) gene; and rs731236 in the VDR gene.
Only the VDR rs731236 variant was considered to have moderate epidemiological credibility, the researchers say, while the other four had weak credibility due to low sample sizes, high heterogeneity, or unaccounted-for bias.
Indeed, in five studies in ethnically diverse populations, the VDR minor allele was consistently protective against LUTS, with an odds ratio of 0.64 versus wild-type.
“Uniquely among statistically significant findings, this association was both consistent across studies, with an adequate pooled sample of the minor allele, and no apparent sources of bias in the primary studies, conferring moderate epidemiological credibility”, write Cartwright et al.
The team concludes: “The currently identified genetic associations explain only a tiny fraction of the heritability. The discovery of further risk variants should both help to explain the complex pathophysiology of these symptoms and provide a route to effective primary prevention.”
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