MR has increasingly been used within the field of drug target validation, testing for on- and off-target effects of a particular drug, whilst providing some evaluation of efficacy. Such an application requires knowledge about the drug target and biological pathway by which the drug influences a particular exposure.
The first examples of such applications occurred within the cardiovascular disease field, whereby inhibitors of certain pathways involved in low-density lipoprotein cholesterol synthesis - including inhibitors of cholesteryl ester transfer protein (CETP) and proprotein convertase subtilisin–kexin type 9 (PCSK9). By targeting the genes that code for those proteins or metabolites in an MR context, it is possible to mimic the activity of such drugs and estimate or predict the efficacy and off-target effects of such drugs before, during or after taken to trials in humans. Therefore, many drug companies are increasingly including such evaluations of drug targets using MR analyses (amongst other human genetic evidence) in the prioritisation of drugs.
References
- Nelson MR, Tipney H, Painter JL, et al. The support of human genetic evidence for approved drug indications. Nat Genet 2015; 47: 856-60.
- Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med 2016; 375: 2144-2153.
- Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk. JAMA 2017; 318: 947-956.
- Wurtz P, Wang Q, Soininen P, et al. Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase. J Am Coll Cardiol 2016; 67: 1200-10.