Abstract for presentation at 11th International Congress of Human Genetics

Identification of GATA2 polymorphisms associated with early onset coronary artery disease

  • Jessica Connelly, Center for Human Genetics, Duke University, Durham, NC, United States
  • Liyong Wang, Center for Human Genetics, Duke University, Durham, NC, United States
  • Carol Haynes, Center for Human Genetics, Duke University, Durham, NC, United States
  • A Brent Hale, Center for Human Genetics, Duke University, Durham, NC, United States
  • Jeffery Vance, Center for Human Genetics, Duke University, Durham, NC, United States
  • William Kraus, Department of Medicine, Duke University, Durham, NC, United States
  • Elizabeth Hauser, Center for Human Genetics, Duke University, Durham, NC, United States
  • Simon Gregory, Center for Human Genetics, Duke University, Durham, NC, United States

    • Six independent coronary artery disease (CAD) genetic screens, including our GENECARD early onset CAD study (Hauser et al. 2005), have identified linkage regions on 11 different chromosomes. Of these, only variants in the ALOX5AP gene (chromosome 13q) have been shown to predispose individuals to myocardial infarction, an outcome of CAD. The most significant linkage peak from our GENECARD linkage study is localized to chromosome 3q13 (multipoint LOD=3.50). GATA2, which localizes within our chromosome 3 linkage peak, was selected as a CAD candidate gene based upon differential gene expression data from distal and proximal regions of the aorta. These analyses identified the expression patterns of the endothelial transcription factor GATA2 as highly predictive of atherosclerosis susceptibility (Seo et al. 2004). We sequenced exons 2-6 of GATA2 and identified 5 novel single nucleotide polymorphisms (SNPs) within the 3’UTR of the gene. Additionally, we genotyped 13 SNPs in our original GENECARD linkage sample (n=420 families), as well as an additional 681 GENECARD families as a validation set. We used APL to analyze our original GENECARD sample set and the complete set of 1101 families to test for family based association between SNPs in GATA2 and early onset CAD. Although we detected no significant association in our original data set, three SNPs, representing the three LD blocks (D’) in GATA2, are associated with affection status in our validation set (p<0.05). Addition of the original GENECARD linkage set to our validation group significantly strengthens the association of these markers, rs2335052, rs2713604, and rs2713579 (p= 0.017, 0.009, 0.005, respectively) and identifies an additional marker in the 3’ UTR, rs3803, which resides within LD block 3 (p=0.022). These SNPs flank or reside within the sixth exon of GATA2, where we have identified five novel polymorphisms. This data suggests that the sixth exon of GATA2 may be important for the etiology of CAD.

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