Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events: A GENIUS-CHD study of individual participant data

Amand F. Schmidt, Chim Lang, Vinicius Tragante, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Akerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehischlegel, Marie-Pierre Dube, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. BraundLutz P. Breitling, Graciela E. Delgado, Nubia E. Duarte, Line Dufresne, Niclas Eriksson, Luisa Foco, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Pekka Kuukasjarvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Ify R. Mordi, Riyaz S. Patel, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha

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Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.
Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103,357 Europeans with established CHD at baseline from the GENIUS-CHD Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/MI), occurred in 13,040 of the 93,115 participants with available outcome data. Effect estimates were compared to case/control risk obtained from CARDIoGRAMPlusC4D including 47,222 CHD cases and 122,264 controls free of CHD.
Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/MI among those with established CHD at baseline (GENIUS-CHD OR 1.02; 95% CI 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D OR 1.20; 95% CI 1.18-1.22; p for interaction <0.001 compared to the GENIUS-CHD estimate.Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (OR 1.07; 95% CI 1.04-1.09).
Conclusions: In contrast to studies comparing individuals with CHD to disease free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
Original languageEnglish
Pages (from-to)161-172
Number of pages12
JournalCirculation: Genomic and Precision Medicine
Issue number4
Early online date21 Mar 2019
Publication statusPublished - Apr 2019



  • chromosome 9p21
  • genetics
  • association studies
  • residual risk
  • prognosis
  • myocardial infarction
  • recurrent event
  • secondary prevention
  • Myocardial infarction
  • Genetic variation
  • Chromosome
  • Risk factor
  • Secondary prevention
  • genetic
  • chromosome
  • risk factor
  • variation

Cite this

Schmidt, A. F., Lang, C., Tragante, V., McCubrey, R. O., Holmes, M. V., Howe, L. J., Direk, K., Akerblom, A., Leander, K., Virani, S. S., Kaminski, K. A., Muehischlegel, J. D., Dube, M-P., Allayee, H., Almgren, P., Alver, M., Baranova, E. V., Behlouli, H., Boeckx, B., ... Pitha, J. (2019). Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events: A GENIUS-CHD study of individual participant data. Circulation: Genomic and Precision Medicine, 12(4), 161-172.