Abstract 618: Identification of Novel Disease Genes for Metabolic Syndrome

Abstract

Factors that underlie the association of diverse traits of the metabolic syndrome have remained largely unknown. The strong heritable nature of this condition provides an exceptional avenue for discovery of the disease mechanisms by using modern techniques of human molecular genetics. Strikingly, efforts by genome-wide association studies to identify common variants that show association with two or more traits have largely failed. Growing evidence indicates excess of rare genetic variants through recent exponential population growth, raising the possibility for their causal role in common diseases. With the advent of high throughput sequencing the power for identification of functional rare variants has dramatically increased. By biasing for extreme phenotypes and utilizing traditional method of segregation analysis we have discovered a number of disease genes for metabolic syndrome and coronary artery disease. A major benefit of this strategy is that true causal relationships has been established between rare variations in a gene, its cognate pathways and the disease of interest. These, in turn, have provided fundamental new insight into pathogenesis of poorly understood diseases such as plaque erosion, and logical starting points for identifying new targets and pathways for therapeutic intervention. By dissecting cognate pathways, we have identified novel targets, including Dyrk1B kinase, a novel incretin and components of Wnt signaling pathway to treat CAD, diabetes and hyperlipidemia and have implemented those succesfuly in animal models.