GATA2 Is Associated with Familial Early-Onset Coronary Artery Disease

Abstract

The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance. Coronary artery disease (CAD) is the most common form of heart disease in the Western world and is one of the leading causes of death in the United States. CAD is inherited and is a complex genetic disease because it results from changes to multiple genes acting in concert with one another and the environment. The authors locate CAD susceptibility genes by convergence of techniques and identify variation within a gene of interest in an early-onset CAD population. If a specific variant is found more often in affected individuals or families than in controls, this can suggest that this gene variant is associated with disease. The authors have identified a gene, GATA2, which is located in a genomic region suspected to contain genes for CAD and displays expression patterns predictive of location of disease within human donor aortas. They have identified several GATA2 variants that segregate with CAD in a family-based early-onset CAD population and have further validated two of these associations in a separate young case-control sample affected with CAD. These data imply that the transcription factor GATA2 may play a role in CAD susceptibility and suggest that the study of GATA2 targets may uncover a set of GATA2-regulated genes important to CAD inheritance.