Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

CARDIoGRAMPlusC4D Consortium

doi:10.1161/CIRCGEN.119.002471

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

CARDIoGRAMPlusC4D Consortium

Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom (R.S.P., J.D., A. Timmis).
Division Heart and Lungs, Department of Cardiology (A.F.S., V.T. D.K., F.W.A.).
Intermountain Heart Institute, Intermountain Medical Center, Salt Lake City, UT (R.O.M., J.F.C., J.B.M., J.L.A.).
National Institute for Health Research Oxford Biomedical Research Centre (M.V.H.), University of Oxford, United Kingdom.
Institute of Cardiovascular Science, Faculty of Population Health Science (R.S.P., A.F.S., L.J.H., K.D., J.D., A.D.H., F.W.A.).
Department of Medical Sciences, Cardiology (A.A., E.H., C.H., D. Lindholm), Uppsala University, Sweden.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (K.L., U.d.F.).
Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Section of Cardiovascular Research, and Department of Medicine, Baylor College of Medicine, Houston, TX (S.S.V., C.M.B.).
Department of Cardiology (K.A.K., A. Szpakowicz).
Harvard Medical School, Boston, MA (J.D.M., M.H. S.C.B.).
Université de Montréal, QC, Canada (M.-P.D.).
Departments of Preventive Medicine and Biochemistry and Molecular Medicine (H.A., J.H.), Keck School of Medicine of USC, Los Angeles, CA.
Department of Clinical Sciences, Lund University, Malmö, Sweden (P.A., O.M.).
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Estonia (M.A., A.M.).
Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre (H.B., L.D., L.P., J.M.B.).
Laboratory for Translational Genetics, VIB Center for Cancer Biology, VIB, Belgium (B.B., D. Lambrechts).
National Institute of Health Research (NIHR) Leicester Biomedical Research Centre (P.S.B., C.P.N.), Glenfield Hospital, Leicester, United Kingdom.
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg (L.P.B., U.M., H.B.).
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.D., M. Kleber, W.M.).
Heart Institute, University of Sao Paulo, Brazil (N.E.D., A.C.P.).
Preventive and Genomic Cardiology, McGill University Health Centre, Montreal, QC, Canada (L.D., J.C.E., G.T.).
Uppsala Clinical Research Center (A.A., N.E., S.J., E.H., C.H., B.L., D. Lindholm, A. Siegbahn, L.W.), Uppsala University, Sweden.
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy (L.F.).
Laboratory of Experimental Cardiology (C.M.G., B.D.H.).
Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.).
Institute for Genetic Medicine (J.H.), Keck School of Medicine of USC, Los Angeles, CA.
Centre for Experimental Medicine, Institut for Clinical and Experimental Medicine, Prague, Czech Republic (J.A.H., J.P.).
Department of Cardio-Thoracic Surgery (P.K.).
Department of Biostatistics and Epidemiology, Texas Heart Institute, Houston (V.-V.L.).
Medical Central Laboratories, Feldkirch, Austria (A.L.).
Department of Genetics, Statistical Genomics Division (P.A.L., S.C.).
Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Scotland, United Kingdom (D. Levin, I.R.M., C.C.L.).
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland (L.-P.L., T.L.).
Department of Medicine, University of Verona, Italy (N. Martinelli, D.G., O.O.).
Department of Cardiology, Heart Center (K.N.).
The Christchurch Heart Institute, University of Otago Christchurch, New Zealand (A.P.B., A.M.R., V.A.C.).
Department of Medical Genetics (R.P.).
Department of Biomedical Informatics (Y.V.S.).
Clinical Epidemiology and Biostatistics (M.W.T.T.).
Department of Cardiovascular Medicine, Heart and Vascular Institute and Center for Clinical Genomics (W.H.W.T.).

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	e002471
Number of pages	12
Journal	Circulation. Genomic and precision medicine
Volume	12
Issue number	4
DOIs	https://doi.org/10.1161/CIRCGEN.119.002471
Publication status	Published - Apr 2019

Keywords

chromosone
genetic variation
myocardial infarction
risk factor
secondary prevention

Access to Document

10.1161/CIRCGEN.119.002471

CIRCGEN.119.002471Final published version, 211 KB

Cite this

@article{a1d852f965904600b51e8d7b5894e3eb,

title = "Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events",

abstract = "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.",

keywords = "chromosone, genetic variation, myocardial infarction, risk factor, secondary prevention",

author = "\{CARDIoGRAMPlusC4D Consortium\} and Patel, \{Riyaz S\} and Schmidt, \{Amand F\} and Vinicius Tragante and McCubrey, \{Raymond O\} and Holmes, \{Michael V\} and Howe, \{Laurence J\} and Kenan Direk and Axel {\AA}kerblom and Karin Leander and Virani, \{Salim S\} and Kaminski, \{Karol A\} and Muehlschlegel, \{Jochen D\} and Marie-Pierre Dub{\'e} and Hooman Allayee and Peter Almgren and Maris Alver and Baranova, \{Ekaterina V\} and Hassan Behlouli and Bram Boeckx and Braund, \{Peter S\} and Breitling, \{Lutz P\} and Graciela Delgado and Duarte, \{Nubia E\} and Line Dufresne and Niclas Eriksson and Luisa Foco and Gijsberts, \{Crystel M\} and Yan Gong and Jaana Hartiala and Mahyar Heydarpour and Hubacek, \{Jaroslav A\} and Marcus Kleber and Daniel Kofink and Pekka Kuukasj{\"a}rvi and Vei-Vei Lee and Andreas Leiherer and Lenzini, \{Petra A\} and Daniel Levin and Leo-Pekka Lyytik{\"a}inen and Nicola Martinelli and Ute Mons and Nelson, \{Christopher P\} and Kjell Nikus and Pilbrow, \{Anna P\} and Rafal Ploski and Sun, \{Yan V\} and Tanck, \{Michael W T\} and Tang, \{W H Wilson\} and Klungel, \{Olaf H\} and \{Maitland-van der Zee\}, \{Anke H\}",

year = "2019",

month = apr,

doi = "10.1161/CIRCGEN.119.002471",

language = "English",

volume = "12",

journal = "Circulation. Genomic and precision medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

TY - JOUR

T1 - Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

AU - CARDIoGRAMPlusC4D Consortium

AU - Patel, Riyaz S

AU - Schmidt, Amand F

AU - Tragante, Vinicius

AU - McCubrey, Raymond O

AU - Holmes, Michael V

AU - Howe, Laurence J

AU - Direk, Kenan

AU - Åkerblom, Axel

AU - Leander, Karin

AU - Virani, Salim S

AU - Kaminski, Karol A

AU - Muehlschlegel, Jochen D

AU - Dubé, Marie-Pierre

AU - Allayee, Hooman

AU - Almgren, Peter

AU - Alver, Maris

AU - Baranova, Ekaterina V

AU - Behlouli, Hassan

AU - Boeckx, Bram

AU - Braund, Peter S

AU - Breitling, Lutz P

AU - Delgado, Graciela

AU - Duarte, Nubia E

AU - Dufresne, Line

AU - Eriksson, Niclas

AU - Foco, Luisa

AU - Gijsberts, Crystel M

AU - Gong, Yan

AU - Hartiala, Jaana

AU - Heydarpour, Mahyar

AU - Hubacek, Jaroslav A

AU - Kleber, Marcus

AU - Kofink, Daniel

AU - Kuukasjärvi, Pekka

AU - Lee, Vei-Vei

AU - Leiherer, Andreas

AU - Lenzini, Petra A

AU - Levin, Daniel

AU - Lyytikäinen, Leo-Pekka

AU - Martinelli, Nicola

AU - Mons, Ute

AU - Nelson, Christopher P

AU - Nikus, Kjell

AU - Pilbrow, Anna P

AU - Ploski, Rafal

AU - Sun, Yan V

AU - Tanck, Michael W T

AU - Tang, W H Wilson

AU - Klungel, Olaf H

AU - Maitland-van der Zee, Anke H

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

KW - chromosone

KW - genetic variation

KW - myocardial infarction

KW - risk factor

KW - secondary prevention

U2 - 10.1161/CIRCGEN.119.002471

DO - 10.1161/CIRCGEN.119.002471

M3 - Article

C2 - 30897348

SN - 2574-8300

VL - 12

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

IS - 4

M1 - e002471

ER -

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Abstract

Keywords

Access to Document

Fingerprint

Cite this