Molecular Determinants of Coronary Artery Disease

Summary

Principal Investigator: Qing Kenneth Wang
Abstract: The most important cause of death and disability in the Western world is atherosclerotic coronary artery disease (CAD) and its primary complication-acute myocardial infarction (MI). The long-term objective of this project is to define genetic pathways and molecular mechanisms for CAD and MI. The central hypothesis of this proposal is that the pathogenesis of CAD/MI involves functional mutations in key genes that perturb the complex molecular processes involved in CAD/MI. To this end, recently, in a large pedigree with autosomal dominant CAD/MI, we identified a specific MEF2A mutation (21-bp deletion) that appears to be responsible for this family's CAD/MI (Science, in press). Furthermore, we have completed a genomewide scan for susceptibility genes for CAD/MI in a well characterized U.S. cohort consisting of 1,163 affected persons in 428 multiplex families with premature CAD and MI (average age at onset: 44.4 + 9.7 years). Of eight novel significant susceptibility loci detected for MI linkage to the chromosomal region lp34-36 showed multipoint allelesharing P values of <10 -12 (LOD = 11.68). The present proposal is driven by these exciting results. The specific aims are: Specific Aim 1: To map and identify a novel CAD/MI gene using single large families and model-based linkage analysis, and positional cloning. First, we will continue to validate our finding that mutations in MEF2A cause familial CAD/MI by characterizing the MEF2A knockout mice and transgenic mice for phenotype related to CAD/MI. A series of molecular and cell biological experiments are designed to explore the molecular mechanisms of the MEF2A deletion. We will also identify SNPs in MEF2A and determine whether some of the SNPs increase or decrease the risk of common complex CAD/MI by association studies. Secondly, we plan to continue to use model-based linkage analysis and positional cloning to map and identify at least one new CAD/MI gene. We have recruited three large and extended CAD/MI pedigrees that are not linked toMEF2A, and each family has statistically sufficient power (simulated LOD scores of 3.53, 7.22, and 6.62, respectively) to conduct a genomewide scan of significant linkage to CAD and MI. Furthermore, 16 families of more than four affected individuals have been identified with an average of 27 living siblings and parents per family for this study. Specific Aim 2: To identify the susceptibility gene for MI on the chromosomal region lp34-36, We will focus on the chromosome lp34-36 MI locus for our follow-up gene discovery effort because this is the most significant linkage identified for MI to date (LOD score of 11.68). We will perform fine mapping, identification of candidate genes, SNP identification and genotyping_ family-TDT analysis (Sibship Disequilibrium Test) as well as population-based case-control studies to determine whether a specific SNP or SNP haplotype in a candidate gene is associated with MI. The accomplishment of research objectives in this proposal has the potential to have a substantial impact on the understanding of the molecular mechanism of CAD and MI, thereby facilitating better prevention, diagnosis and therapy.
Funding Period: 2004-08-01 - 2004-12-31
more information: NIH RePORT

Top Publications

  1. pmc Association of SNP rs17465637 on chromosome 1q41 and rs599839 on 1p13.3 with myocardial infarction in an American caucasian population
    Annabel Z Wang
    Center for Cardiovascular Genetics, Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Hum Genet 75:475-82. 2011
  2. pmc Multi-allelic haplotype association identifies novel information different from single-SNP analysis: a new protective haplotype in the LRP8 gene is against familial and early-onset CAD and MI
    Gong Qing Shen
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, USA
    Gene 521:78-81. 2013
  3. pmc Advances in the genetic basis of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute ND4 38, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Curr Atheroscler Rep 7:235-41. 2005
  4. pmc Molecular genetics of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Curr Opin Cardiol 20:182-8. 2005
  5. pmc Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis
    A A Timur
    Center for Molecular Genetics, ND40, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Cell Mol Life Sci 62:1434-47. 2005
  6. ncbi Ferritin in atherosclerosis
    Sun Ah You
    Center for Molecular Genetics, Department of Molecular Cardiology, ND4 38, Lerner Research Institute, and Center for Cardiovascular Genetics, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Clin Chim Acta 357:1-16. 2005
  7. pmc Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28
    A Melamud
    J Med Genet 43:e27. 2006
  8. pmc An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction
    Gong Qing Shen
    Department of Molecular Cardiology, Lerner Research Institute, Center for Cardiovascular Genetics, Cleveland, OH 44195, USA
    Am J Hum Genet 81:780-91. 2007
  9. pmc Identification and functional characterization of a novel splicing mutation in RP gene PRPF31
    Jing Yu Liu
    Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
    Biochem Biophys Res Commun 367:420-6. 2008

Scientific Experts

  • Qing Kenneth Wang
  • Gong Qing Shen
  • Lin Li
  • Annabel Z Wang
  • Eric J Topol
  • Domenico Girelli
  • Oliviero Olivieri
  • Jing Yu Liu
  • A Melamud
  • A A Timur
  • Sun Ah You
  • Qiuyun Chen
  • Nicola Martinelli
  • Bin Zhang
  • Xin Cui
  • Xiaohua Dai
  • Zhaohui Tang
  • Xin Tu
  • Yan Bai
  • Jiqun Sheng
  • Mugen Liu
  • Xu Wang
  • Xueqing Jiang
  • Ying Hu
  • Chun Fan
  • John Barnard
  • Susan Henderson
  • Kandice Marchant
  • Robert Elston
  • Stanley L Hazen
  • Roberto Corrocher
  • Edward F Plow
  • Sara B Seidelmann
  • Quansheng Xi
  • Jeong Euy Park
  • Shaoqi Rao
  • Jing Li
  • June Cassano
  • G Q Shen
  • N S Peachey
  • H Zegarra
  • D Chung
  • Q Xi
  • L Li
  • S A Hagstrom
  • E I Traboulsi
  • E Simpson
  • D J Driscoll

Detail Information

Publications9

  1. pmc Association of SNP rs17465637 on chromosome 1q41 and rs599839 on 1p13.3 with myocardial infarction in an American caucasian population
    Annabel Z Wang
    Center for Cardiovascular Genetics, Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Hum Genet 75:475-82. 2011
    ..05). Our results establish two SNPs, rs17465637 in MIA3 and rs599839 near SORT1 as significant risk factors for MI in the American Genebank Caucasian population...
  2. pmc Multi-allelic haplotype association identifies novel information different from single-SNP analysis: a new protective haplotype in the LRP8 gene is against familial and early-onset CAD and MI
    Gong Qing Shen
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, USA
    Gene 521:78-81. 2013
    ..001). These results suggest that a common LRP8 haplotype TCCGC confers a significant protective effect on the development of familial, early-onset CAD and/or MI...
  3. pmc Advances in the genetic basis of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute ND4 38, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Curr Atheroscler Rep 7:235-41. 2005
    ..These studies identify a new mechanism, the myocyte enhancer factor 2 (MEF2) signaling pathway of vascular endothelium, for the pathogenesis of CAD, and also confirm the role of inflammation in the disease process...
  4. pmc Molecular genetics of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Curr Opin Cardiol 20:182-8. 2005
    ..Many advances have recently been made, however, and these are reviewed here...
  5. pmc Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis
    A A Timur
    Center for Molecular Genetics, ND40, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Cell Mol Life Sci 62:1434-47. 2005
    ....
  6. ncbi Ferritin in atherosclerosis
    Sun Ah You
    Center for Molecular Genetics, Department of Molecular Cardiology, ND4 38, Lerner Research Institute, and Center for Cardiovascular Genetics, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Clin Chim Acta 357:1-16. 2005
    ..Future studies will determine whether increased ferritin levels can serve as a distinct biomarker for the incidence of CAD/MI and distinguish whether increased ferritin levels are a cause of CAD or a consequence of the disease process...
  7. pmc Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28
    A Melamud
    J Med Genet 43:e27. 2006
    ..06, 2.17, and 2.20, respectively. Haplotype analysis revealed segregation of the disease phenotype with markers at Xq28...
  8. pmc An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction
    Gong Qing Shen
    Department of Molecular Cardiology, Lerner Research Institute, Center for Cardiovascular Genetics, Cleveland, OH 44195, USA
    Am J Hum Genet 81:780-91. 2007
    ..This extensive study, involving multiple independent populations, provides the first evidence that genetic variants in LRP8 may contribute to the development of premature and familial CAD and MI...
  9. pmc Identification and functional characterization of a novel splicing mutation in RP gene PRPF31
    Jing Yu Liu
    Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
    Biochem Biophys Res Commun 367:420-6. 2008
    ..Our studies identify a novel splicing mutation in PRPF31 associated with adRP and suggest that the penetrance of RP11 mutations may be correlated with the expression level of the PRPF31 mRNA...