Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development

Drug development in cardiovascular disease is stagnating, with lack of validated targets a major roadblock to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization (MR). Such genetic support can increase the probability of a clinical trial succeeding. MR is being widely applied to quantitative traits (e.g. adiposity and blood lipids) with the aim of identifying risk factors for disease that are both causal and amenable to therapeutic modification. However, there are important differences between genetic investigations of a biomarker (such as HDL-cholesterol) and a drug target that seeks to modify the same biomarker of interest (such as CETP), with implications on the methodology, interpretation and applications of MR to drug development. Differences include the comparative nature of the genetic architecture, i.e. that of a biomarker typically being polygenic, whereas that for a protein drug target being monogenic. and the potential for drug targets to show pleiotropic disease associations which may differ to those of the biomarker it is designed to modify. In this review, we compare and contrast the role of MR as applied to quantitative traits versus drug targets, describing differences between approaches and the function each plays. Our review will put into context findings emerging from this burgeoning field of scientific investigation, with the aim of clarifying the aetiological roles of biomarkers in disease, prioritizing candidate drug targets based on genetic-guided credibility of causation and in so doing, improve the odds of success in the drug development pipeline.