Genetic biomarkers associated with risk and therapeutic response in erectile dysfunction: a systematic review

Erectile dysfunction (ED) is a multifactorial condition influenced by vascular, neuroendocrine, metabolic, and psychological factors. Growing evidence suggests that genetic variation may contribute to individual susceptibility, severity, and therapeutic response, particularly regarding nitric oxide (NO) signaling and vascular pathways. To systematically synthesize evidence on genetic biomarkers associated with the risk, severity, or therapeutic response of ED in adult men.

A systematic review was conducted following PRISMA 2020 guidelines and registered in PROSPERO (CRD420251144891). Searches were performed in MEDLINE, Embase, Scopus, LILACS, and Web of Science. Observational studies evaluating genetic polymorphisms or related biomarkers in adult men with Erectile dysfunction were included. Two reviewers independently screened studies, extracted data, and assessed methodological quality using JBI tools and the certainty of evidence using GRADE.

Thirty-five studies met inclusion criteria. The genetic markers most frequently investigated involved pathways related to nitric oxide synthesis and endothelial function, including NOS3 (eNOS), NOS1, PDE5A, VEGF, ACE, ARG1/ARG2, DDAH1/2, and MTHFR. Functional variants-particularly NOS3 G894T, T-786C, and the intron 4 VNTR-were commonly associated with increased ED susceptibility, earlier onset, or greater severity, though results varied across populations. Several polymorphisms influenced pharmacological response to PDE5i, especially variants in PDE5A, VEGF, eNOS, ARG1/2, and DDAH. However, methodological limitations were pervasive: 77.8% of studies had moderate risk of bias, and 80.6% showed low certainty of evidence. Only one study reached moderate certainty.

Current evidence suggests that genetic polymorphisms related to nitric oxide signaling, vascular regulation, and PDE5 inhibitor pharmacodynamics are associated with variability in erectile dysfunction risk and treatment response. However, the overall certainty of evidence is low, and further validation in well-designed, multiethnic studies is required before clinical translation.