The Potential to Inform Statin Use in Multiple Sclerosis Through Human Genetics
Asli Buyukkurt, Adil Harroud · Neurology · 2023
Less than 10% of drugs that enter phase 1 clinical development ultimately receive regulatory approval, often due to shortcomings in safety or efficacy. The recognition that drugs with genetically supported targets have a two-fold higher approval rate has led to the incorporation of human genetic approaches in drug development.1 One such approach is Mendelian randomization (MR), which uses genetic variants to enable causal inference between exposures and outcomes. These exposures can be complex traits, such as body mass index, or in the context of drug discovery, levels of genes, or proteins. For instance, genetic variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene region that predispose individuals to higher or lower levels of low-density lipoprotein (LDL) cholesterol can predict the effect of HMGCR inhibitors (statins) on cardiovascular disease.2 This genetically mimics statin exposure and can provide insight into the efficacy, adverse effects, and repurposing potential of these and other therapeutics. Because allocation to genetic variation in levels of the exposure (e.g., LDL cholesterol) is random and set at conception, MR reduces the risk of confounding and reverse causality and provided key assumptions are met, can mirror randomized clinical trials at a much lower cost.3