Location of Repository

Genomewide Association Analysis of Coronary Artery Disease

By Nilesh J. Samani, Jeanette Erdmann, Alistair S. Hall, Christian Hengstenberg, Massimo Mangino, Bjoern Mayer, Richard J. Dixon, Thomas Meitinger, Peter S. Braund, H.-Erich Wichmann, Jennifer H. Barrett, Inke R. König, Suzanne E. Stevens, Silke Szymczak, David-Alexandre Tregouet, Mark M. Iles, Friedrich Pahlke, Helen Pollard, Wolfgang Lieb, Francois Cambien, Marcus Fischer, Willem Ouwehand, Stefan Blankenberg, Anthony J. Balmforth, Andrea Baessler, Stephen G. Ball, Tim M. Strom, Ingrid Brænne, Christian Gieger, Panos Deloukas, Martin D. Tobin, Andreas Ziegler, John R. Thompson, Heribert Schunkert, Wellcome Trust Case Control Consortium and Cardiogenics Consortium

Abstract

Background - Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. \ud \ud Methods - We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). \ud \ud Results - Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10–14 and P=3.40x10–6, respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10–5 and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10–6) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). \ud \ud Conclusions - We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease

Publisher: Massachusetts Medical Society
Year: 2007
DOI identifier: 10.1056/NEJMoa072366
OAI identifier: oai:lra.le.ac.uk:2381/7338
Journal:

Suggested articles

Preview

Citations

  1. for the WTCCC and the Cardiogenics Consortium* A bs tr ac t From the University of Leicester, doi
  2. (2004). Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet doi
  3. (1994). Genetic susceptibility to death from coronary heart disease in a study of twins. doi
  4. What genome-wide association studies can do for medicine. doi
  5. (2007). Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature doi
  6. A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study. doi
  7. Effect of a common X-linked angiotensin II type 2-receptor gene polymorphism (−1332 G/A) on the occurrence of premature myocardial infarction and stenotic atherosclerosis requiring revascularization. Atherosclerosis doi
  8. A comprehensive linkage analysis for myocardial infarction and its related risk factors. doi
  9. Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction. Circulation 2005;111:855-62. doi
  10. resource for population genetics, controls and a broad spectrum of disease phenotypes. doi
  11. Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. doi
  12. A common allele on chromosome 9 associated with coronary heart disease. doi
  13. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007;316:1491-3. Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles.
  14. (1994). p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. doi
  15. Smad expression in human atherosclerotic lesions: evidence for impaired TGFbeta/Smad signaling in smooth muscle cells of fibrofatty lesions. doi
  16. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
  17. (2007). Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science
  18. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
  19. Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. doi
  20. Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase. Arch Biochem Biophys 2005;442:196-205. Randak doi
  21. Three siblings with nonketotic hyperglycinaemia, mildly elevated plasma homocysteine concentrations and moderate methylmalonic aciduria. J Inherit Metab Dis 2000;23:520-2. Fruchart
  22. Genetic analysis of the interleukin-18 system highlights the role of the interleukin18 gene in cardiovascular disease. doi
  23. (1999). Identification of a novel mouse p53 target gene DDA3. Oncogene doi
  24. function and clinical relevance of MIA (melanoma inhibitory activity). doi
  25. Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control. doi
  26. TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev 2000;11:15-22. Libby doi
  27. of coronary artery disease. doi
  28. The future of genetic studies of complex human diseases. Science 1996;273:1516-7. Morgan TM, Krumholz HM, Lifton RP, Spertus JA. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.