Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events
Authors: Patel Riyaz S. , Schmidt Amand F. , Tragante Vinicius , McCubrey Raymond O. , Holmes Michael V. , Howe Laurence J. , Direk Kenan , Åkerblom Axel , Leander Karin , Virani Salim S. , Kaminski Karol A. , Muehlschlegel Jochen D. , Dubé Marie-Pierre , Allayee Hooman , Almgren Peter , Alver Maris , Baranova Ekaterina V. , Behlouli Hassan , Boeckx Bram , Braund Peter S. , Breitling Lutz P. , Delgado Graciela , Duarte Nubia E. , Dufresne Line , Eriksson Niclas , Foco Luisa , Gijsberts Crystel M. , Gong Yan , Hartiala Jaana , Heydarpour Mahyar , Hubacek Jaroslav A. , Kleber Marcus , Kofink Daniel , Kuukasjärvi Pekka , Lee Vei-Vei , Leiherer Andreas , Lenzini Petra A. , Levin Daniel , Lyytikäinen Leo-Pekka , Martinelli Nicola , Mons Ute , Nelson Christopher P. , Nikus Kjell , Pilbrow Anna P. , Ploski Rafal , Sun Yan V. , Tanck Michael W.T. , Tang W.H.Wilson , Trompet Stella , van der Laan Sander W. , van Setten Jessica , Vilmundarson Ragnar O. , Viviani Anselmi Chiara , Vlachopoulou Efthymia , Boerwinkle Eric , Briguori Carlo , Carlquist John F. , Carruthers Kathryn F. , Casu Gavino , Deanfield John , Deloukas Panos , Dudbridge Frank , Fitzpatrick Natalie , Gigante Bruna , James Stefan , Lokki Marja-Liisa , Lotufo Paulo A. , Marziliano Nicola , Mordi Ify R. , Muhlestein Joseph B. , Newton Cheh Chris , Pitha Jan , Saely Christoph H. , Samman-Tahhan Ayman , Sandesara Pratik B. , Teren Andrej , Timmis Adam , Van de Werf Frans , Wauters Els , Wilde Arthur A.M. , Ford Ian , Stott David J. , Algra Ale , Andreassi Maria G. , Ardissino Diego , Arsenault Benoit J. , Ballantyne Christie M. , Bergmeijer Thomas O. , Bezzina Connie R. , Body Simon C. , Bogaty Peter , de Borst Gert J. , Brenner Hermann , Burkhardt Ralph , Carpeggiani Clara , Condorelli Gianluigi , Cooper-DeHoff Rhonda M. , Cresci Sharon , de Faire Ulf , Doughty Robert N. , Drexel Heinz , Engert James C. , Fox Keith A.A. , Girelli Domenico , Hagström Emil , Hazen Stanley L. , Held Claes , Hemingway Harry , Hoefer Imo E. , Hovingh G. Kees , Johnson Julie A. , de Jong Pim A. , Jukema J. Wouter , Kaczor Marcin P. , Kähönen Mika , Kettner Jiri , Kiliszek Marek , Klungel Olaf H. , Lagerqvist Bo , Lambrechts Diether , Laurikka Jari O. , Lehtimäki Terho , Lindholm Daniel , Mahmoodi Bakhtawar K. , Maitland-van der Zee Anke H. , McPherson Ruth , Melander Olle , Metspalu Andres , Pepinski Witold , Olivieri Oliviero , Opolski Grzegorz , Palmer Colin N. , Pasterkamp Gerard , Pepine Carl J. , Pereira Alexandre C. , Pilote Louise , Quyyumi Arshed A. , Richards A. Mark , Sanak Marek , Scholz Markus , Siegbahn Agneta , Sinisalo Juha , Smith J. Gustav , Spertus John A. , Stewart Alexandre F.R. , Szczeklik Wojciech , Szpakowicz Anna , ten Berg Jurriën M. , Thanassoulis George , Thiery Joachim , van der Graaf Yolanda , Visseren Frank L.J. , Waltenberger Johannes ,   CARDIoGRAMPlusC4D Consortium, Van der Harst Pim , Tardif Jean-Claude , Sattar Naveed , Lang Chim C. , Pare Guillaume , Brophy James M. , Anderson Jeffrey L. , März Winfried , Wallentin Lars , Cameron Vicky A. , Horne Benjamin D. , Samani Nilesh J. , Hingorani Aroon D. , Asselbergs Folkert W. 
Published: April 2019

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.