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.

Figure 1. Schematic of the GATA2 Gene Structure

The 12 SNPs representing predicted LD bins in GATA2 are shown in black; the five novel SNPs identified through sequencing are shown in grey. † and * indicate a synonymous and nonsynonymous SNP, respectively.

Figure 2. Pairwise LD between GATA2 SNPs

LD was estimated in one unaffected Caucasian individual from each nonredundant GENECARD discordant sibling pair (n = 279). A similar pattern of LD was observed using the matched probands.