Abstract 15938: Identification of a Novel Disease Gene for Early Onset Atherosclerosis, Diabetes and Metabolic Syndrome by Whole Exome Sequencing and Linkage Analysis
Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. A cluster of highly heritable risk factors known as metabolic syndrome is a major and growing predisposing factor for development of CAD, however the genetic factors that underlies their association is not well known. In this Study, Several remotely related kindreds with autosomal dominant early onset CAD, juvenile-onset truncal obesity, severe hypertension, and type II diabetes mellitus were ascertained from a nomadic population of Iran, known for extremely high rate of early onset CAD. All affected and unaffected family members were genotyped, using Illumina SNP genechip. Analysis of linkage under dominant model mapped the disease gene to a small segment of chromosome 19q13 with a maximum lod score > 6. Next generation sequencing identified one single missense mutation in Dyrk1B gene (R102C) within the linked interval that perfectly segregated with the disease. Functional characterization of the mutation revealed a gain of function in pathways related to adipogenesis and gluconeogenesis. Subsequently, a second mutation (H90P) was identified in another unrelated kindred with early onset CAD and metabolic syndrome. Dyrk1BH90P similarly increased G6pase expression in vitro, consistent with a gain of function effect. Taken together, these findings suggest that Dyrk1B regulates adipogenesis and gluconeogenesis and its mutations cause early onset atherosclerosis, metabolic syndrome and obesity by a gain of function mechanism.
- © 2013 by American Heart Association, Inc.