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126 CHROMOSOME 9P21 LOCUS AND ANGIOGRAPHIC CORONARY ARTERY DISEASE BURDEN: A COLLABORATIVE META-ANALYSIS
  1. K Chan1,
  2. R S Patel2,
  3. P Newcombe3,
  4. C P Nelson4,
  5. A Qasim5,
  6. S E Epstein5,
  7. S Burnett5,
  8. V L Vaccarino6,
  9. A M Zafari7,
  10. S H Shah8,
  11. J L Anderson9,
  12. J F Carlquist9,
  13. J Hartiala10,
  14. H Allayee10,
  15. K Hinohara11,
  16. B S Lee12,
  17. A Erl13,
  18. K L Ellis14,
  19. A Goel15,
  20. A S Schaefer16,
  21. N E Mokhtari16,
  22. B A Goldstein17,
  23. M A Hlatky17,
  24. A S Go18,
  25. G Q Shen19,
  26. Y Gong20,
  27. C Pepine20,
  28. R C Laxton1,
  29. J C Wittaker21,
  30. W H W Tang22,
  31. J A Johnson20,
  32. Q K Wang19,
  33. T L Assimes17,
  34. U Nöthlings23,
  35. M Farrall15,
  36. H Watkins15,
  37. A M Richards14,
  38. V A Cameron14,
  39. A Muendlein24,
  40. H Drexel24,
  41. W Koch13,
  42. J E Park12,
  43. A Kimura11,
  44. W F Shen25,
  45. I A Simpson26,
  46. S L Hazen22,
  47. B D Horne9,
  48. E R Hauser8,
  49. A A Quyyumi27,
  50. M P Reilly5,
  51. N J Samani28,
  52. S Ye1
  1. 1 William Harvey Research Institute, Barts and the London School of Medicine and Dentistry
  2. 2 Research Institute, Barts and the London School of Medicine and Dentistry
  3. 3 MRC biostatistics unit
  4. 4 Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease
  5. 5 Cardiovascular Institute, the Perelman School of Medicine at the University of Pennsylvania
  6. 6 Department Epidemiology, Emory University Rollins School of Public Health
  7. 7 Department Epidemiology, Emory University Rollins School of Public Health
  8. 8 Center for Human Genetics, Department of Medicine, Duke University
  9. 9 Intermountain Heart Institute, Intermountain Medical Center
  10. 10 Department of Preventive Medicine, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California
  11. 11 Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University
  12. 12 Division of Cardiology, Samsung Medical Center, Sung Kyun Kwan University School of Medicine
  13. 13 German Heart Centre Munich
  14. 14 Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago
  15. 15 Wellcome Trust Centre for Human Genetics, University of Oxford
  16. 16 Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel
  17. 17 Department of Medicine, Stanford University of Medicine
  18. 18 Division of Research, Kaiser Permanente
  19. 19 Department of Molecular Cardiology, Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Cleveland Clinic
  20. 20 University of Florida, Health Science Center
  21. 21 London School of Hygiene and Tropical Medicine
  22. 22 The Center for Cardiovascular Diagnostics & Prevention, Cleveland Clinic
  23. 23 Section for Epidemiology, Institute for Experimental Medicine, Christian-Albrechts-University of Kiel
  24. 24 Vorarlberg Institute for Vascular Investigation & Treatment
  25. 25 Department of Cardiology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine
  26. 26 Wessex Regional Cardiac Unit, Southampton University Hospital
  27. 27 Department of Medicine, Emory University School of Medicine
  28. 28 Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital

    Abstract

    Background Chromosome 9p21 variants have been strongly associated with coronary heart disease in genome-wide association studies, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. We investigated the relationship of 9p21 locus with (1) angiographic coronary artery disease (CAD) burden and (2) myocardial infarction (MI) in individuals with underlying CAD. Methods:We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data were provided for each cohort on the presence and burden of angiographic CAD; MI cases with underlying CAD; and the diabetic status of all subjects.

    Results We first confirmed an association between 9p21 and CAD using angiographically defined cases and controls (pooled OR=1.31 (95% CI 1.20 to 1.43)). Among subjects with angiographic CAD (n=20,987), random-effects model identified an association with multi-vessel CAD, compared to those with single-vessel disease (OR=1.10 (95% CI 1.04 to 1.17) per copy of risk allele). Genotypic models showed an OR of 1.15 (95% CI 1.04 to 1.26) for heterozygous carrier and 1.23 (95% CI 1.08 to 1.39) for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n=17 791) and controls (n=15 882) had underlying CAD (OR=0.99 (95% CI 0.95 to 1.03) per risk allele).

    Conclusions The 9p21 locus shows convincing association with greater burden of CAD, but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

    Figure 1

    Association between 9p21 and multi-vessel disease as compared with single-vessel disease (Analysed with allelic Model, D+L Overall=Random effect analysis, Bayesian Overall=Bayesian analysis).

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