Abstract 17862: Protection From Acute Myocardial Infarction in Humans is Associated With a Genetic Variation Near a Novel Gene Encoding a Human Protein Binding to a Mouse Model of Vulnerable Plaque
Introduction: Human vulnerable plaque (VP) has certain unique phenotypic features. We developed a mouse model with atherosclerotic lesions containing many of these features, and then used a unique phage display library derived from human bone marrow cDNA to fish, in vivo, for proteins preferentially binding to VP. We identified 11 such ligands, each encoded by previously unknown genes and each preferentially expressed in bone marrow stem/progenitor cells.
Hypothesis: Reasoning that these novel ligands may play a role in stem cell homing and thereby in plaque stability/vulnerability, we hypothesized that genetic variations in these ligands alter the propensity of plaques to rupture.
Methods: We characterized the genetic variation (SNPs) present within +/−100KB of the binding sequences (736 SNPs) using Affymetrix 6.0 SNP chips. SNP associations were initially tested in a coronary angiographically phenotyped cohort collected by Washington Hospital Center (n=454 CAD but no MI; n=420 CAD with MI).
Results: Thirteen SNPs located in six different loci were identified and then tested in a larger cohort of individuals with angiographically identified CAD (CAD and MI, n=4,852; CAD but no MI, n=2,914). One variant (8p22) protected individuals from MI (p = 0.002) with an odds ratio = 0.66 (95% CI: 0.52 to 0.85) after correction for the 13 SNPs.
Conclusions: Our phage fishing strategy, using a human bone marrow-derived cDNA library to fish for ligands in a unique mouse model of VP, led to identification of previously unrecognized genes encoding novel VP-binding ligands that, through genetic association, revealed a SNP protective against MI in individuals with angiographically documented CAD. The variant needs to be explored for a possible function not only on the novel gene but other genes in the 8p22 region. This finding could have important clinical implications for prognostic stratification; also, identification of VP binding ligands could lead to targeted imaging of and drug delivery to the VP.
- © 2010 by American Heart Association, Inc.