Discovery and validation of new molecular targets in treating dyslipidemia: the role of human genetics

Abstract

Several high-profile failures of lipid-related therapeutics in clinical trials have led to intense interest in improved discovery and preclinical prioritization of potential targets. The careful study of patients with rare monogenic disorders has played a key role in establishing the causal role of cholesterol in atherosclerosis and highlighting viable drug targets. Systematic efforts to extend the association of common variants linked with lipid levels to coronary disease enable assessment of the vascular consequences of lifelong differences in lipids due to variation in specific molecules. This application of genetic epidemiology, termed Mendelian randomization, may prove useful in informing ongoing drug development efforts.

Figure 1. Selected applications of Mendelian randomization

Mendelian randomization analyses require robust associations between 1) a genetic variant and an intermediate phenotype; and 2) the intermediate phenotype and disease. If this relationship is causal, the genetic variant should related to disease as well. This evidence for causality has been confirmed for variants affecting both LDL and Lipoprotein(a) levels (A and B), but not C-reactive protein (CRP) (C).