Genetically proxied inhibition of Phosphodiesterase-5 and cancer risks: A drug-target Mendelian randomization...

Area of Science:

• Genetics
• Pharmacology
• Oncology

Background:

• Observational studies present conflicting evidence on the association between phosphodiesterase 5 (PDE5) inhibitor use and cancer risk.
• The causal relationship between PDE5 inhibition and cancer development remains unclear, necessitating further investigation.

Purpose of the Study:

• To investigate the potential causal effect of PDE5 inhibition on the risk of developing various cancers.
• To utilize a 2-sample cis-Mendelian randomization (MR) approach to clarify the relationship between PDE5A protein levels and cancer incidence.

Main Methods:

• Employed a 2-sample cis-Mendelian randomization (MR) analysis using single-nucleotide polymorphisms (SNPs) in the PDE5A gene as genetic instruments.
• Analyzed summary-level data from genome-wide association studies (GWAS) for 22 cancer types, including discovery (UKB-PPP) and replication (FinnGen) cohorts.
• Utilized inverse-variance weighted random-effects models for primary analysis, with adjustments for multiple testing.

Main Results:

• Genetically predicted lower PDE5A protein levels were associated with a reduced risk of colorectal cancer (OR=0.80, P=6.15×10⁻¹¹).
• A significant association was observed between genetically proxied PDE5 inhibition and a decreased risk of gastric cancer (OR=0.48, P=4.70×10⁻⁵).
• No significant associations were found for the other 20 cancer types studied.

Conclusions:

• Genetically proxied PDE5 inhibition demonstrates a protective effect against colorectal cancer and gastric cancer.
• This MR study provides genetic evidence supporting the long-term safety profile of PDE5 inhibitors concerning cancer risk.
• Findings highlight the potential for drug repurposing of PDE5 inhibitors in the treatment or prevention of colorectal and gastric cancers.