ABSTRACT
OBJECTIVES: The purpose of this study was to test the hypothesis that 9p21 gene dosage determines the severity of coronary artery disease (CAD). BACKGROUND: The 9p21 locus is the first common genetic variant to associate with risk of CAD and/or myocardial infarction in multiple studies. METHODS: A cross-sectional study examined nondiabetic patients with CAD defined by coronary angiography to have at least 1 epicardial stenosis >50%. In all, 950 patients with early onset CAD (age 56.1 +/- 9.6 years) and an independent sample of 764 patients with late onset CAD (age 70.0 +/- 8.0 years) were enrolled from the cardiac catheterization laboratories at the University of Ottawa Heart Institute from April 15, 2006, to August 15, 2008, and genotyped for the single nucleotide polymorphism rs1333049 9p21 risk variant. Angiographers were blinded to genotype. The association between 9p21 risk genotype and the proportion of patients with 3-vessel disease, 1-vessel disease, left main trunk disease, and coronary artery bypass graft surgery was tested, as was its association with the modified Gensini and Duke coronary scoring indexes. RESULTS: Among younger CAD cases, 3-vessel disease demonstrated a strong, direct association with 9p21 gene dosage (p = 4.26 x 10(-4)). Conversely, 1-vessel disease demonstrated a strong inverse association with increasing gene dosage (p = 2.41 x 10(-5)). In the replication sample, gene dosage also predicted 3-vessel disease (p = 6.51 x 10(-6)). Left main trunk disease and coronary artery bypass graft surgery demonstrated a direct strong association with gene dosage (p = 3.66 x 10(-4)) and (p = 2.42 x 10(-2)), respectively. Gene dosage demonstrated a strong, direct association with both the modified Gensini (p < 0.0001) and modified Duke (p = 3 x 10(-4)) coronary scores. Risk variant 9p21 did not associate with myocardial infarction once stratified for disease severity. CONCLUSIONS: Gene dosage of the common risk variant 9p21 predicts the severity of coronary atheromatous burden.
Subject(s)
Chromosomes, Human, Pair 9/genetics , Coronary Artery Disease/genetics , Gene Dosage , Genetic Predisposition to Disease/epidemiology , Risk Assessment/methods , Severity of Illness Index , Age Factors , Age of Onset , Aged , Coronary Angiography , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/epidemiology , Cross-Sectional Studies , Electrocardiography , Female , Follow-Up Studies , Genetic Variation , Genotype , Humans , Male , Middle Aged , Ontario/epidemiology , Prevalence , Retrospective Studies , Risk FactorsABSTRACT
The transcription factor GATA2 was reported to associate with coronary artery disease (CAD) in the family-based Genecard sample (Connelly et al. in PLoS Genet 2:e139, 2006). We asked whether GATA2 associates with sporadic cases of CAD in the Ottawa Heart Genomics Study (OHGS) and Cleveland Clinic (CC) populations. We genotyped the lead single nucleotide polymorphism (SNP) from Genecard, rs2713604 which is located in intron 5-6 of GATA2 in 600 CAD cases and 625 controls, as well as a tag SNP rs1573949 (r (2) = 0.87 in Caucasians of European ancestry in Utah from HapMap) in 1,136 cases and 1,162 controls in the OHGS1 population. A further 1,838 CAD cases and 913 controls derived from an independent sample combining genotypes from CC and OHGS2 populations were genotyped for rs1573949. Neither of the genotyped SNPs associates with CAD in the OHGS1 or CC/OHGS2 populations. Our data suggest that GATA2 does not contribute to the development of angiographic CAD among sporadic cases.
