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

• Published in: Circulation: Genomic and Precision Medicine
• Main Authors: Patel, RS, Schmidt, AF, Tragante, V, McCubrey, RO, Holmes, MV, Howe, LJ, Direk, K, Åkerblom, A, Leander, K, Virani, SS, Kaminski, KA, Kuukasjärvi, P, Lee, V-V, Leiherer, A, Lenzini, PA, Levin, D, Lyytikäinen, L-P, Martinelli, N, Mons, U, Nelson, CP, Nikus, K, Drexel, H, Pilbrow, AP, Ploski, R, Sun, YV, Tanck, MWT, Tang, WHW, Trompet, S, van der Laan, SW, Van Setten, J, Vilmundarson, RO, Viviani Anselmi, C, Engert, JC, Vlachopoulou, E, Boerwinkle, E, Briguori, C, Carlquist, JF, Carruthers, KF, Casu, G, Deanfield, J, Deloukas, P, Dudbridge, F, Fitzpatrick, N, Fox, KAA, Gigante, B, James, S, Lokki, M-L, Lotufo, PA, Marziliano, N, Mordi, IR, Muhlestein, JB, Newton-Cheh, C, Pitha, J, Saely, CH, Girelli, D, Samman-Tahhan, A, Sandesara, PB, Teren, A, Timmis, A, Van de Werf, F, Wauters, E, Wilde, AAM, Ford, I, Stott, DJ, Algra, A, Hagström, E, Andreassi, MG, Ardissino, D, Arsenault, BJ, Ballantyne, CM, Bergmeijer, TO, Bezzina, CR, Body, SC, Bogaty, P, de Borst, GJ, Brenner, H, Hazen, SL, Burkhardt, R, Carpeggiani, C, Condorelli, G, Cooper-DeHoff, RM, Cresci, S, de Faire, U, Doughty, RN, Held, C, Hemingway, H, Hoefer, IE, Hovingh, GK, Muehlschlegel, JD, Johnson, JA, de Jong, PA, Jukema, JW, Kaczor, MP, Kähönen, M, Kettner, J, Kiliszek, M, Klungel, OH, Lagerqvist, B, Lambrechts, D, Dubé, M-P, Laurikka, JO, Lehtimäki, T, Lindholm, D, Mahmoodi, BK, Maitland-van der Zee, AH, McPherson, R, Melander, O, Metspalu, A, Pepinski, W, Olivieri, O, Allayee, H, Opolski, G, Palmer, CN, Pasterkamp, G, Pepine, CJ, Pereira, AC, Pilote, L, Quyyumi, AA, Richards, AM, Sanak, M, Scholz, M, Almgren, P, Siegbahn, A, Sinisalo, J, Smith, JG, Spertus, JA, Stewart, AFR, Szczeklik, W, Szpakowicz, A, Ten Berg, JM, Thanassoulis, G, Thiery, J, Alver, M, van der Graaf, Y, Visseren, FLJ, Waltenberger, J, Van der Harst, P, Tardif, J-C, Sattar, N, Lang, CC, Paré, G, Brophy, JM, Anderson, JL, Baranova, EV, März, W, Wallentin, L, Cameron, VA, Horne, BD, Samani, NJ, Hingorani, AD, Asselbergs, FW, Behlouli, H, Boeckx, B, Braund, PS, Breitling, LP, Delgado, G, Duarte, NE, Dufresne, L, Eriksson, N, Foco, L, Gijsberts, CM, Gong, Y, Hartiala, J, Heydarpour, M, Hubacek, JA, Kleber, M, Kofink, D
• Format: Article in Journal/Newspaper
• Language: English
• Published: American Heart Association, Lippincott, Williams & Wilkins 2019
• Subjects: chromosome; genetic variation; myocardial infarction; risk factor; secondary prevention; Nunavut; Yukon; Canada; New Zealand; British Columbia; Myers; Charity; Abbott; Stanton; Collard
• Online Access: https://www.ahajournals.org/doi/10.1161/CIRCGEN.119.002471; http://hdl.handle.net/2381/44554; https://doi.org/10.1161/CIRCGEN.119.002471

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCGEN.119.002471. 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 (Coronary Disease Cohort Study) and PMI (Post Myocardial Infarction Study) were funded by the Health Research Council and Heart Foundation of New Zealand; Dr Samman-Tahnan is supported by the National Institutes of Health/ National Institutes of Aging grant AG051633; Dr Sandesara is supported by the Abraham J. & Phyllis Katz Foundation (Atlanta, GA); The Emory Cardiovascular Biobank is supported by NIH grants 5P01HL101398-02, 1P20HL113451-01, 1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-01, 1U10HL110302-01, 1DP3DK094346-01, 2P01HL086773-06A1; this Estonian Biobank was funded by EU H2020 grant 692145, Estonian Research Council Grant IUT20-60, IUT24-6, PUT1660, PUT735 and European Union through the European Regional Development Fund Project No.2014-2020.4.01.15-0012 GENTRANSMED, NIH-GIANT, ERA-CVD grant Detectin-Heart failure and 2R01DK075787-06A1; GENESIS-PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond-Premature Acute Coronary Syndrome) is funded by the Canadian Institutes of Health Research and Heart and Stroke Foundations of Alberta, NWT & Nunavut, British Columbia and Yukon, Nova Scotia, Ontario, and Quebec (HSFC); The GENDEMIP study (Genetic Determination of Myocardial Infarction in Prague) was supported by Project (MH, Czech Republic) No. 00023001 (Institute of Clinical and Experimental Medicine, Prague); GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. C.N.P. has received grant funding from the Wellcome Trust to develop the GoDARTS cohort; Dr Mordi is supported by an NHS Education of Scotland/Chief Scientist Office Postdoctoral Clinical Lectureship (PCL 17/07); the GENECOR study (Genetic Mapping for Assessment of Cardiovascular Risk) was supported in part by the Italian Ministry of Research’s Fund for Basic Research (FIRB 2005); GRACE (Global Registry of Acute Coronary Events–Belgium) UK was supported in part by an Educational Grant from Sanofi Aventis; Award from Chief Scientist Office, Scotland; INVEST-GENES (International Verapamil SR Trandolopril Study Genetic Substudy) was supported by the National Institute of Health Pharmacogenomics Research Network grant U01-GM074492, NIH R01 HL074730, University of Florida Opportunity Fund, BASF Pharma and Abbott Laboratories; Italian Atherosclerosis, Thrombosis and Vascular Biology Group was supported by Epidemiologia e Genetica della Morte Improvvisa in Sardegna; The KAROLA study has received financial support by the German Ministry of Education and Research (01GD9820/0 and 01ER0814), by the Willy-Robert-Pitzer Foundation, and by the Waldburg-Zeil Clinics Isny; The KRAKOW GENIUS Study was supported by a grant from the Polish Ministry of Science and Higher Education, no. NN402083939 and the National Science Centre, no. 2013/09/B/NZ5/00770; LIFE-Heart was funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by funds of the Free State of Saxony within the framework of the excellence initiative; The LURIC study (The Ludwigshafen Risk and Cardiovascular Health Study) was supported by the Seventh Framework Program (AtheroRemo, grant agreement number 201668 and RiskyCAD (Personalized Diagnostics and Treatment of High Risk Coronary Artery Disease Patients), grant agreement number 305739) of the European Union; The NEAPOLIS CAMPANIA (Neapolis Campania Italia) study was suppported by European Research Council Advanced Grant (CardioEpigen, no. 294609);Italian Ministry of Health (PE-2013-02356818);Italian Ministry of Education, University and Research (2015583WMX); The North East Poland Myocardial Infarction Study was supported by grant N N 402 529139 from the National Science Center (Poland); Dr Vilmundarson is supported by a graduate fellowship of the University of Ottawa Heart Institute; OHGS (Ottawa Heart Genomics Study) was funded in part by a Heart and Stroke Foundation grant; Dr Stott was supported in part by an investigator initiated grant from Bristol Myers Squibb USA; The PROSPER study (Prospective Study of Pravastatin in the Elderly at Risk) was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Dr Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810); The RISCA (Recurrance and Inflammation in the Acute Coronary Syndromes Study) was supported in part by FRSQ, HSFC, Merck Frost Canada, Pfizer Canada; The SHEEP study (Stockholm Heart Epidemiology Program) was supported by grants from the Swedish Council for Work Life and Social Research, and the Stockholm County Council; The TNT trial (Treating to New Targets) was sponsored by Pfizer who granted access to data, Genotyping of the samples was funded in part by grants from Genome Canada and Genome Quebec and the Canadian Institutes of Health Research (CIHR); Dr Arsenault holds a junior scholar award from the Fonds de recherche du Quebec- Sante (FRQS); Dr Cresci is supported, in part, by the National Institutes of Health (Cresci R01 NR013396). The TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patient’s Health Status) was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113; The Utrecht Cardiovascular Pharmacogenetics Study studies were funded by the Netherlands Heart Foundation and the Dutch Top Institute Pharma Mondriaan Project; The Verona Heart Study was supported by the Cariverona Foundation; Veneto Region; Italian Ministry of Education, University, and Research (MIUR); LURM (Laboratorio Universitario di Ricerca Medica) Research Center, University of Verona; The Warsaw ACS Registry (acute coronary syndrome) is supported by grant N R13 0001 06 from The National Centre for Research and Development (NCBiR), Statutory Grant from Medical University of Warsaw; Dr Nelson is funded by the British Heart Foundation; Prof. Samani is funded by the British Heart Foundation and is a NIHR Senior Investigator. Prof Hingorani is a NIHR Senior Investigator; Prof Asselbergs is supported by University College London Hospitals NIHR Biomedical Research Centre, EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant n° 116074, the European Union’s Horizon 2020 research and innovation programme under the ERA-NET Co-fund action N°01KL1802 (Druggable-MI-gene) jointly funded by the Dutch Heart Foundation and Netherlands Organization for Health Research and Development (ZonMw). Peer-reviewed Publisher Version