Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data.
Patel, Riyaz S. MD ,,*; Schmidt, Amand F. PhD ,,*; Tragante, Vinicius PhD ,*; McCubrey, Raymond O. MS; Holmes, Michael V. MD, PhD; Howe, Laurence J. PhD; Direk, Kenan PhD; Akerblom, Axel MD, PhD; Leander, Karin PhD; Virani, Salim S. MD, PhD; Kaminski, Karol A. MD, PhD; Muehlschlegel, Jochen D. MD, MMSc; Dube, Marie-Pierre PhD; Allayee, Hooman PhD; Almgren, Peter MSc; Alver, Maris MSc; Baranova, Ekaterina V. MSc; Behlouli, Hassan PhD; Boeckx, Bram PhD; Braund, Peter S. PhD; Breitling, Lutz P. MD; Delgado, Graciela MSc; Duarte, Nubia E. PhD; Dufresne, Line MSc; Eriksson, Niclas PhD; Foco, Luisa PhD; Gijsberts, Crystel M. MD, PhD; Gong, Yan PhD; Hartiala, Jaana PhD; Heydarpour, Mahyar PhD; Hubacek, Jaroslav A. DSc; Kleber, Marcus PhD; Kofink, Daniel PhD; Kuukasjarvi, Pekka MD, PhD; Lee, Vei-Vei MS; Leiherer, Andreas PhD; Lenzini, Petra A. MS; Levin, Daniel PhD; Lyytikainen, Leo-Pekka MD; Martinelli, Nicola MD, PhD; Mons, Ute PhD; Nelson, Christopher P. PhD; Nikus, Kjell MD, PhD; Pilbrow, Anna P. PhD; Ploski, Rafal MD, PhD; Sun, Yan V. PhD; Tanck, Michael W.T. PhD; Tang, W.H.Wilson MD; Trompet, Stella PhD; van der Laan, Sander W. PhD; van Setten, Jessica; Vilmundarson, Ragnar O. MSc; Viviani Anselmi, Chiara PhD; Vlachopoulou, Efthymia PhD; Boerwinkle, Eric PhD; Briguori, Carlo MD, PhD; Carlquist, John F. PhD; Carruthers, Kathryn F. MPhil; Casu, Gavino MD; Deanfield, John MD; Deloukas, Panos PhD; Dudbridge, Frank PhD; Fitzpatrick, Natalie MSc; Gigante, Bruna MD, PhD; James, Stefan MD, PhD; Lokki, Marja-Liisa PhD; Lotufo, Paulo A. MD, PhD; Marziliano, Nicola PhD; Mordi, Ify R. MD; Muhlestein, Joseph B. MD; Newton Cheh, Chris MD; Pitha, Jan PhD; Saely, Christoph H. MD; Samman-Tahhan, Ayman MD; Sandesara, Pratik B. MD; Teren, Andrej MD; Timmis, Adam MD; Van de Werf, Frans PhD; Wauters, Els PhD; Wilde, Arthur A.M. MD, PhD; Ford, Ian MD, PhD; Stott, David J. MD; Algra, Ale MD; Andreassi, Maria G. PhD; Ardissino, Diego MD; Arsenault, Benoit J. PhD; Ballantyne, Christie M. MD; Bergmeijer, Thomas O. MD; Bezzina, Connie R. PhD; Body, Simon C. MD, MPH, MBChB; Bogaty, Peter MD; de Borst, Gert J. MD; Brenner, Hermann MD, PhD; Burkhardt, Ralph MD; Carpeggiani, Clara MD, PhD; Condorelli, Gianluigi MD, PhD; Cooper-DeHoff, Rhonda M. PharmD; Cresci, Sharon MD; de Faire, Ulf PhD; Doughty, Robert N. MD; Drexel, Heinz MD; Engert, James C. PhD; Fox, Keith A.A. MD, PhD; Girelli, Domenico MD, PhD; Hagstrom, Emil MD, PhD; Hazen, Stanley L. MD, PhD; Held, Claes MD, Ph; Hemingway, Harry MD, PhD; Hoefer, Imo E. MD, PhD; Hovingh, G. Kees MD, PhD; Johnson, Julie A. PharmD; de Jong, Pim A. MD; Jukema, J. Wouter MD, PhD; Kaczor, Marcin P. MD, PhD; Kahonen, Mika PhD; Kettner, Jiri PhD; Kiliszek, Marek MD, PhD; Klungel, Olaf H. PharmD, PhD; Lagerqvist, Bo MD, PhD; Lambrechts, Diether PhD; Laurikka, Jari O. MD, PhD; Lehtimaki, Terho PhD; Lindholm, Daniel MD, PhD; Mahmoodi, Bakhtawar K. MD, PhD; Maitland-van der Zee, Anke H. PharmD, PhD; McPherson, Ruth MD, PhD; Melander, Olle MD, PhD; Metspalu, Andres MD, PhD; Pepinski, Witold MD, PhD; Olivieri, Oliviero MD; Opolski, Grzegorz MD, PhD; Palmer, Colin N. PhD; Pasterkamp, Gerard MD, PhD; Pepine, Carl J. MD; Pereira, Alexandre C. MD, PhD; Pilote, Louise MD; Quyyumi, Arshed A. MD; Richards, A. Mark MD, PhD; Sanak, Marek MD, PhD; Scholz, Markus PhD; Siegbahn, Agneta MD, PhD; Sinisalo, Juha MD, PhD; Smith, J. Gustav MD, PhD; Spertus, John A. MD, MPH; Stewart, Alexandre F.R. PhD; Szczeklik, Wojciech MD, PhD; Szpakowicz, Anna MD, PhD; ten Berg, Jurrien M. MD, PhD; Thanassoulis, George MD; Thiery, Joachim MD; van der Graaf, Yolanda MD; Visseren, Frank L.J. MD; Waltenberger, Johannes; CARDIoGRAMPlusC4D Consortium; Van der Harst, Pim MD, PhD; Tardif, Jean-Claude MD; Sattar, Naveed PhD; Lang, Chim C. MD; Pare, Guillaume MD; Brophy, James M. MD; Anderson, Jeffrey L. MD; Marz, Winfried MD; Wallentin, Lars MD, PhD; Cameron, Vicky A. PhD; Horne, Benjamin D. PhD, MPH; Samani, Nilesh J. MD, PhD ,+; Hingorani, Aroon D. MD, PhD ,+; Asselbergs, Folkert W. MD, PhD ,,,,+
Circulation: Genomic and Precision Medicine.
12(4):e002471, April 2019.
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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 (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 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/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with 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 (odds ratio, 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.
(C) 2019 American Heart Association, Inc.