Genetic predisposition is a factor in 40-70% of cases of benign prostatic hyperplasia (BPH) and voiding symptoms. However, informal reviews summarizing genes and variants imparting genetic disposition to BPH are not yet available.
We conducted an informal narrative review of genes and variants associated with BPH or voiding symptoms in candidate gene studies, genome-wide association studies (GWAS), and Mendelian randomization studies. A literature search of PubMed was performed using the terms "BPH heritability", "LUTS heritability", "BPH risk variant", "LUTS genetic risk", "GWAS BPH", and "genome-wide BPH".
Candidate gene studies focused on variants related to the vitamin D receptor, steroid metabolism, detoxification, inflammation, cytokines, and growth factors, which were previously found to be associated with prostate cancer. Despite overall limited conclusiveness of candidate gene approaches, some recent studies point to population-dependent contributions of single variants to genetic BPH predisposition. Four GWAS and two Mendelian randomization studies for BPH identified correlation of BPH and voiding symptoms with variants related to testosterone, prostate-specific antigen, progesterone, transcription factors, the cell cycle, neuronal organization, and thyroid-stimulating hormone.
The drug targetability of most of the genes identified in the BPH setting is precluded by predictable unbalanced side effects, low efficacy, unknown organ specificity, and a lack of characterization in the prostate. Meta-analyses of GWAS are not yet available for BPH. Unless calculated using quantitative approaches, specific contributions of the risk variants identified to the overall risk of BPH remain uncertain.
While age is a risk factor for benign enlargement of the prostate in all affected patients, genetic factors may be involved in 39-72% of patients. Research has identified a number of possible risk genes, but is still at a very early stage. It is unlikely that drugs could be used to target these genes because of expected side effects that would be tolerated for cancer treatment, but not for benign diseases, or low efficacy in previous clinical trials.
European urology open science. 2024 Oct 31*** epublish ***
Martin Hennenberg, Sheng Hu, Alexander Tamalunas, Christian G Stief
Department of Urology, LMU University Hospital, LMU Munich, Munich, Germany.