Abstract 15390: Diverse Functional Effects of GWAs CAD Risk Genes in Mice: CardioGENE KO-Project
Coronary artery disease (CAD) is a complex disease. Recently, more than 35 genomic loci have been shown to be associated with CAD on a genome-wide significance level. Up to now, only genes related to lipid (LDL, VLDL) and inflammation (9p21 locus, cytokines) have been verified and their pathophysiological mechanisms further evaluated in mice. We aim to investigate the effect of deleting CAD risk genes in mouse models to transfer knowledge from genome-wide association studies (GWAs) to functional in vivo studies. Firstly, studies were conducted to identify potential effects of global gene deletion on growth, fertility, viability and behavior in these mice. Secondly, additional cardiovascular phenotyping screens including in-vivo vascular injury models as well as in-vitro migration and proliferation assays were applied. Thirdly, KO mice were backcrossed into a proatherogenic background (ApoE- or Ldlr-KO-mice) to study the development of atherosclerotic lesions. Observational screens as well as preliminary functional data for Mras, Adamts-7, Cxcl12, Cyp17a1, Ppap2b, Zc3hc1, and Gucy1a3 KO mice exhibit distinct phenotypes. Mras deficient mice display metabolic dysfunction and an impaired migration of B-cells. ADAMTS-7 plays a key role in the extracellular degradation leading to enhanced neointima formation after vascular injury. Gucy1a3-KO mice presented with loss of NO mediated inhibition of platelet aggregation. Zc3hc1-KO-mice lacking the encoding NIPA protein, involved in cell cycle, display abnormal viability and markedly decreased body weight. Cyp17a1 encodes for a member of the cytochrome P450 superfamily of enzymes, which are involved in cholesterol synthesis, drug and steroid metabolisms. Cyp17a1-KO-mice have abnormal steroid metabolism and display congenital adrenal hyperplasia. Cxcl12 and Ppap2b deficiency is lethal. Deletion of each of the CAD risk genes in mice leads to high variability of phenotypes. Traditional risk factors such as hypercholesterolemia or hypertension are only involved in some mice deficient for CAD risk genes. These results suggest a diverse array of cellular functions exerted by newly identified CAD risk genes which reflects the complex mechanisms leading to CAD.
- © 2012 by American Heart Association, Inc.