Abstract 1436: Gene Dosage of the Common Variant 9p21 Predicts Severity of Coronary Atheromatous Burden
Background: The first common genetic risk variant for coronary artery disease (CAD), 9p21, was recently identified and shown to occur in 75% of Caucasian and Asian populations. However, 9p21 does not contain a protein coding gene and its function is unknown. Given the phenotypes of atherosclerosis and thrombosis, pursuit of the molecular mechanisms mediating 9p21 risk requires elucidation of the 9p21 phenotype. Accordingly, we tested the hypothesis that 9p21 is directly related to coronary atherosclerosis.
Methods: We studied 709 patients who were prospectively enrolled from the coronary catheterization laboratory at the University of Ottawa Heart institute from April 15th 2006 to 4th January 2008. Each subject was genotyped for the single nucleotide polymorphism rs1333049 (risk allele located at 9p21). Patients were designated AA (risk/risk), AB (risk/non-risk) and BB (non-risk/non-risk). Angiograms were reviewed by two independent parties blinded to genotype. Lesions with 50% or more stenosis were considered significant for the purposes of this study. Odds ratios were generated for proportion of patients with 3VD, significant left main disease and CABG relative to the non-risk genotype, BB.
Results: We demonstrated a strong direct association between 9p21 gene dosage and 3VD (Fig. 1A⇓). Conversely, a strong inverse association between 9p21 gene dosage and 1VD was observed (Fig. 1B⇓). A strong direct association between gene dosage and LM disease (Fig. 1C⇓) and CABG (Fig. 1D⇓) was seen.
Conclusions: The 9p21 variant risk is mediated through deposition of coronary atheroma. Therefore, elucidating 9p21 function should target atherogenesis.