Phenotyping Patient-Derived Cells for Translational Studies in Cardiovascular Disease

Studies of the genetics of cardiovascular disease and its risk factors have identified many chromosomal loci that contribute to cardiovascular traits. When combining the outcomes of these studies with the findings from basic, hypothesis-driven research, we now have a much clearer outline of the genes that contribute to cardiovascular traits (the parts list), including many that were unsuspected on the basis of candidate gene approaches. The discovery of so many disease loci promises to remake our understanding of disease mechanisms and susceptibility. Particularly exciting is the prospect that new biomarkers of cardiovascular risk can be identified that are orthogonal to traditional cardiac risk factors; ie, they confer risk through mechanisms that are largely independent of traditional risk factors. The existence of such orthogonal risk factors is suggested by the observation that 15% to 20% of patients presenting with coronary disease have no traditional risk factors.1However, the clinical translation of these discoveries faces several challenges. First, the cellular and pathophysiologic significance of most susceptibility alleles is unknown, especially for those at previously unannotated loci. Furthermore, it is not obvious how to integrate an individuals' genotype at multiple disease loci with their environmental exposures to arrive at an assessment of individual disease risk; doing so requires not only clinical studies, but also basic investigations into how disease genes are organized into pathways and networks. In the therapeutic realm, studies are just beginning to examine how genotypic information can inform the choice and dosing of medications. More broadly, generalizable approaches are needed to identify genes and pathways that can best be targeted for therapeutic effect.Addressing these translational roadblocks requires patient-focused investigations, and experimental systems in which the effects of disease alleles can be studied under their native physiological regulatory mechanisms, as well. Patient-derived cells may be well suited to address …