Abstract
Dipender Gill and Stephen Burgess discuss the accompanying study by James Yarmolinsky and colleagues investigating the associations between genetically-proxied inhibition of antihypertensive drug targets and risk of common cancer subtypes using Mendelian randomization.
Highlights
Proteins represent the majority of drug targets; genetic variants affecting the function or expression of genes encoding these proteins can be used as proxies for investigating the effect of pharmacologically perturbing the corresponding protein drug target [1]
This is a critical experiment for corroborating the findings of mendelian randomization analyses performed to investigate the effect of drug target perturbation because it provides evidence to support that any identified association is not attributable to genetic confounding through a variant in linkage disequilibrium [4]
While the association between genetically proxied angiotensin converting enzyme (ACE) inhibition and colorectal cancer risk replicated in the independent FinnGen consortium that is made up of European genetic ancestry individuals, it was not observed when studying a Japanese population
Summary
The evolution of mAenUd:ePlialenasreannodteothmatiazaspteiorPnLfOorSstyle; investigating drug effects. Provided that the genetic proxy can only influence an outcome through its effect on the protein drug target and not some pleiotropic pathway, a genetic association with the outcome can serve as evidence for a potential effect of drug target perturbation on that outcome. This paradigm spawned the field of “drug target mendelian randomization,” which has been used to prioritize the design of clinical trials for more than a decade [2]. In the accompanying study in PLOS Medicine by Yarmolinsky and colleagues [3], genetic variants were identified to proxy the effect of different antihypertensive drug classes and were leveraged in drug target mendelian randomization analyses to explore effects on risk of common cancer subtypes
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