Genetics and Erectile Dysfunction: Leveraging Early Foundations for New Discoveries - Beyond the Abstract

There is a growing interest to identify genetic factors contributing to the development of erectile dysfunction (ED). Since the early pedigree and twin studies suggested a genetic contribution to ED, a number of follow-up candidate gene studies have strengthened these associations. Candidate gene polymorphisms have been identified in endothelial nitric oxide synthase (eNOS), Angiotensin Converting Enzyme (ACE), the androgen receptor, transforming growth factor-b1 (TGF-b1), and methylenetetrahydrofolate reductase (MTHFR). However, these studies are often difficult to reproduce given the variability between study populations. 


Genome-wide association studies (GWAS) have been able to address many of the challenges of candidate gene studies. GWAS uses millions of genetic variants from individual genomes from large cohorts to identify genotype-phenotype associations. Recent GWAS studies have identified loci adjacent to SIM1 involved in the leptin melanocortin signaling pathway, which may confer increased ED risk. With more powerful and cost-effective methods to interrogate the genome, epigenome, transcriptome, and proteome, we expect an accelerated development of novel biomarkers and drug targets for ED. Although our understanding of the genetics of ED is limited, we envision a therapeutic revolution for ED similar to discoveries in other disease processes such as diabetes, with the discovery of zinc-transporter antagonists as novel Type II diabetes treatment.  Since their introduction, PDE5 inhibitors have remained the cornerstone of non-invasive ED therapies, but an “omics” revolution is poised to change this paradigm. Developing cell lines, animal models and functional assays capable of delving into these pathways is essential for this future work. In this comprehensive review, we explore the current literature supporting a genetic contribution to ED and describe a roadmap to the development of novel discoveries and therapeutics in this field.

Written by: Darshan P. Patel, MD, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT.

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