Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events

A GENIUS-CHD study of individual participant data

Amand F. Schmidt, Chim Lang, Vinicius Tragante, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Akerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehischlegel, Marie-Pierre Dube, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. Braund & 30 others Lutz P. Breitling, Graciela E. Delgado, Nubia E. Duarte, Line Dufresne, Niclas Eriksson, Luisa Foco, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Pekka Kuukasjarvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Ify R. Mordi, Riyaz S. Patel, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha

Research output: Contribution to journalArticle

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 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 <0.001 compared to 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 (OR 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 languageEnglish
Number of pages25
JournalCirculation: Genomic and Precision Medicine
Volume12
Issue number4
Early online date21 Mar 2019
DOIs
Publication statusPublished - Apr 2019

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Coronary Disease
Chromosomes
Atherosclerotic Plaques
Disease Progression
Meta-Analysis
Cause of Death
Myocardial Infarction

Keywords

  • chromosome 9p21
  • genetics
  • association studies
  • residual risk
  • prognosis
  • myocardial infarction
  • recurrent event
  • secondary prevention

Cite this

Schmidt, Amand F. ; Lang, Chim ; Tragante, Vinicius ; McCubrey, Raymond O. ; Holmes, Michael V. ; Howe, Laurence J. ; Direk, Kenan ; Akerblom, Axel ; Leander, Karin ; Virani, Salim S. ; Kaminski, Karol A. ; Muehischlegel, Jochen D. ; Dube, Marie-Pierre ; Allayee, Hooman ; Almgren, Peter ; Alver, Maris ; Baranova, Ekaterina V. ; Behlouli, Hassan ; Boeckx, Bram ; Braund, Peter S. ; Breitling, Lutz P. ; Delgado, Graciela E. ; 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 ; Kuukasjarvi, 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 ; Mordi, Ify R. ; Patel, Riyaz S. ; Muhlestein, Joseph B. ; Newton-Cheh, Christopher ; Pitha, Jan. / Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events : A GENIUS-CHD study of individual participant data. In: Circulation: Genomic and Precision Medicine. 2019 ; Vol. 12, No. 4.
@article{01d8feddcd3841dd936773748a9ccf14,
title = "Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events: A GENIUS-CHD study of individual participant data",
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 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 <0.001 compared to 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 (OR 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 = "chromosome 9p21, genetics, association studies, residual risk, prognosis, myocardial infarction, recurrent event, secondary prevention",
author = "Schmidt, {Amand F.} and Chim Lang and Vinicius Tragante and McCubrey, {Raymond O.} and Holmes, {Michael V.} and Howe, {Laurence J.} and Kenan Direk and Axel Akerblom and Karin Leander and Virani, {Salim S.} and Kaminski, {Karol A.} and Muehischlegel, {Jochen D.} and Marie-Pierre Dube 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 Delgado, {Graciela E.} 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 Kuukasjarvi 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 Mordi, {Ify R.} and Patel, {Riyaz S.} and Muhlestein, {Joseph B.} and Christopher Newton-Cheh and Jan Pitha",
year = "2019",
month = "4",
doi = "10.1161/CIRCGEN.119.002471",
language = "English",
volume = "12",
journal = "Circulation: Genomic and Precision Medicine",
issn = "2574-8300",
publisher = "Lippincott, Williams & Wilkins",
number = "4",

}

Schmidt, AF, Lang, C, Tragante, V, McCubrey, RO, Holmes, MV, Howe, LJ, Direk, K, Akerblom, A, Leander, K, Virani, SS, Kaminski, KA, Muehischlegel, JD, Dube, M-P, Allayee, H, Almgren, P, Alver, M, Baranova, EV, Behlouli, H, Boeckx, B, Braund, PS, Breitling, LP, Delgado, GE, Duarte, NE, Dufresne, L, Eriksson, N, Foco, L, Gijsberts, CM, Gong, Y, Hartiala, J, heydarpour, M, Hubacek, JA, Kleber, M, Kofink, D, Kuukasjarvi, P, Lee, V-V, Leiherer, A, Lenzini, PA, Levin, D, Lyytikäinen, L-P, Martinelli, N, Mons, U, Nelson, CP, Nikus, K, Pilbrow, AP, Ploski, R, Mordi, IR, Patel, RS, Muhlestein, JB, Newton-Cheh, C & Pitha, J 2019, 'Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events: A GENIUS-CHD study of individual participant data', Circulation: Genomic and Precision Medicine, vol. 12, no. 4. https://doi.org/10.1161/CIRCGEN.119.002471

Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events : A GENIUS-CHD study of individual participant data. / Schmidt, Amand F.; Lang, Chim; Tragante, Vinicius; McCubrey, Raymond O.; Holmes, Michael V.; Howe, Laurence J.; Direk, Kenan; Akerblom, Axel; Leander, Karin; Virani, Salim S.; Kaminski, Karol A.; Muehischlegel, Jochen D.; Dube, Marie-Pierre; Allayee, Hooman; Almgren, Peter; Alver, Maris; Baranova, Ekaterina V.; Behlouli, Hassan; Boeckx, Bram; Braund, Peter S.; Breitling, Lutz P.; Delgado, Graciela E.; 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; Kuukasjarvi, 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; Mordi, Ify R.; Patel, Riyaz S. (Lead / Corresponding author); Muhlestein, Joseph B.; Newton-Cheh, Christopher; Pitha, Jan.

In: Circulation: Genomic and Precision Medicine, Vol. 12, No. 4, 04.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association of Chromosome 9p21 with Subsequent Coronary Heart Disease events

T2 - A GENIUS-CHD study of individual participant data

AU - Schmidt, Amand F.

AU - Lang, Chim

AU - Tragante, Vinicius

AU - McCubrey, Raymond O.

AU - Holmes, Michael V.

AU - Howe, Laurence J.

AU - Direk, Kenan

AU - Akerblom, Axel

AU - Leander, Karin

AU - Virani, Salim S.

AU - Kaminski, Karol A.

AU - Muehischlegel, Jochen D.

AU - Dube, 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 E.

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 - Kuukasjarvi, 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 - Mordi, Ify R.

AU - Patel, Riyaz S.

AU - Muhlestein, Joseph B.

AU - Newton-Cheh, Christopher

AU - Pitha, Jan

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 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 <0.001 compared to 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 (OR 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 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 <0.001 compared to 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 (OR 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 - chromosome 9p21

KW - genetics

KW - association studies

KW - residual risk

KW - prognosis

KW - myocardial infarction

KW - recurrent event

KW - secondary prevention

U2 - 10.1161/CIRCGEN.119.002471

DO - 10.1161/CIRCGEN.119.002471

M3 - Article

VL - 12

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

SN - 2574-8300

IS - 4

ER -