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Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data.

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posted on 2019-06-21, 15:12 authored by RS Patel, AF Schmidt, V Tragante, RO McCubrey, MV Holmes, LJ Howe, K Direk, A Åkerblom, K Leander, SS Virani, KA Kaminski, P Kuukasjärvi, V-V Lee, A Leiherer, PA Lenzini, D Levin, L-P Lyytikäinen, N Martinelli, U Mons, CP Nelson, K Nikus, H Drexel, AP Pilbrow, R Ploski, YV Sun, MWT Tanck, WHW Tang, S Trompet, SW van der Laan, J Van Setten, RO Vilmundarson, C Viviani Anselmi, JC Engert, E Vlachopoulou, E Boerwinkle, C Briguori, JF Carlquist, KF Carruthers, G Casu, J Deanfield, P Deloukas, F Dudbridge, N Fitzpatrick, KAA Fox, B Gigante, S James, M-L Lokki, PA Lotufo, N Marziliano, IR Mordi, JB Muhlestein, C Newton-Cheh, J Pitha, CH Saely, D Girelli, A Samman-Tahhan, PB Sandesara, A Teren, A Timmis, F Van de Werf, E Wauters, AAM Wilde, I Ford, DJ Stott, A Algra, E Hagström, MG Andreassi, D Ardissino, BJ Arsenault, CM Ballantyne, TO Bergmeijer, CR Bezzina, SC Body, P Bogaty, GJ de Borst, H Brenner, SL Hazen, R Burkhardt, C Carpeggiani, G Condorelli, RM Cooper-DeHoff, S Cresci, U de Faire, RN Doughty, C Held, H Hemingway, IE Hoefer, GK Hovingh, JD Muehlschlegel, JA Johnson, PA de Jong, JW Jukema, MP Kaczor, M Kähönen, J Kettner, M Kiliszek, OH Klungel, B Lagerqvist, D Lambrechts, M-P Dubé, JO Laurikka, T Lehtimäki, D Lindholm, BK Mahmoodi, AH Maitland-van der Zee, R McPherson, O Melander, A Metspalu, W Pepinski, O Olivieri, H Allayee, G Opolski, CN Palmer, G Pasterkamp, CJ Pepine, AC Pereira, L Pilote, AA Quyyumi, AM Richards, M Sanak, M Scholz, P Almgren, A Siegbahn, J Sinisalo, JG Smith, JA Spertus, AFR Stewart, W Szczeklik, A Szpakowicz, JM Ten Berg, G Thanassoulis, J Thiery, M Alver, Y van der Graaf, FLJ Visseren, J Waltenberger, P Van der Harst, J-C Tardif, N Sattar, CC Lang, G Paré, JM Brophy, JL Anderson, EV Baranova, W März, L Wallentin, VA Cameron, BD Horne, NJ Samani, AD Hingorani, FW Asselbergs, H Behlouli, B Boeckx, PS Braund, LP Breitling, G Delgado, NE Duarte, L Dufresne, N Eriksson, L Foco, CM Gijsberts, Y Gong, J Hartiala, M Heydarpour, JA Hubacek, M Kleber, D Kofink
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 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.


The funder(s) of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Within GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease), all participating investigators and sponsors who contributed data and analyses are acknowledged irrespective of academic or industry affiliations. Specific funding statements: Dr Patel is funded by a British Heart Foundation Intermediate Fellowship (FS/14/76/30933). This research was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; Dr Schmidt is funded by BHF grant PG/18/5033837; Dr Holmes works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre; The AGNES study (Arrhythmia Genetics in the Netherlands) was supported by research grants from the Netherlands Heart Foundation (2001D019, 2003T302, 2007B202 and the PREDICT project (CVON 2012-10)), the Leducq Foundation (grant 05-CVD) and the Center for Translational Molecular Medicine (CTMM COHFAR); The Cleveland Clinic Genebank Study was supported in part by NIH (National Institutes of Health) grants R0133169, R01ES021801, R01MD010358, and R01ES025786, R01HL103866, R01DK106000, R01HL126827, P20HL113452, P01HL098055, P01HL076491, and R01HL103931; The 4C study (Clinical Cohorts in Coronary disease Collaboration) was supported in part by NIHR and Barts Charity; The Corogene study was supported by grants from Aarno Koskelo Foundation, Helsinki University Central Hospital special government funds (EVO no. TYH7215, no. TKK2012005, no. TYH2012209, no. TYH2014312), and Finnish Foundation for Cardiovascular research; CABGenomics was supported by Stanton Shernan, C. David Collard, Amanda A. Fox/R01 HL 098601 National Heart Long and Blood Institute; The CDCS



Circulation: Genomic and Precision Medicine, 2019, 12:e002471

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Circulation: Genomic and Precision Medicine


American Heart Association, Lippincott, Williams & Wilkins



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