Effect of genetically proxied use of PDE5 inhibitors on risk of CHD: A drug target Mendelian Randomization study

Background and aim There have been previous and recent studies generating conflicting findings on effect of phosphodiesterase 5 (PDE5) inhibitors with CHD, Diabetes, breast cancer and prostatic cancer. Since we intended to use naturally occurring variation in genes encoding PDE5 to investigate association between genetically proxied PDE5 inhibitors and them. Method We used drug target mendelian randomization as main analytical method. 60,801 cases and 123,504 controls from 48 GWAS studies, mainly European ancestry (77%) for CHD were included. Inverse-variance weighted (IVW) random-effects model was employed as the primary analysis method to estimate the causal effect. And several robust methods were also used to detect the causal association as sensitive analysis. What’s more, colocalization analysis was also applied to verify the association. Result We observed strong evidence for the causal effect of genetically proxied PDE5 inhibitors on decreased CHD risk (IVW method, OR 1.22, 95% confidence interval (95%CI) 1.14-1.29, p-value=7.16E-07). Colocalization analysis also proved the association (H4=99.99%). Besides, we found weak association between genetically proxied inhibition of PDE5 and lower risk of breast cancer as well as prostatic cancer. At last, we found no evidence for effect of PDE5 inhibitors on risk of Diabetes. Conclusion We performed a drug target mendelian randomization supporting that use of PDE5 inhibitors is associated with lower risk of CHD. Though in 1990s studies found frustrating effect of PDE5 inhibitors on curing CHD, future RCT studies can focus on protective effect of PDE5 inhibitors on CHD. Our result may enlighten clinical use of PDE5 inhibitors.