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Genetic variation in PCAF, a key mediator in epigenetics, is associated with reduced vascular morbidity and mortality: evidence for a new concept from three independent prospective studies
  1. Douwe Pons1,2,3,
  2. Stella Trompet1,4,
  3. Anton J M de Craen4,
  4. Peter E Thijssen5,
  5. Paul H A Quax3,5,
  6. Margreet R de Vries5,
  7. Rutger J Wierda3,6,
  8. Peter J van den Elsen3,6,7,
  9. Pascalle S Monraats1,
  10. Mark M Ewing1,3,
  11. Bastiaan T Heijmans8,
  12. P Eline Slagboom8,
  13. Aeilko H Zwinderman9,
  14. Pieter A F M Doevendans2,10,
  15. René A Tio2,11,
  16. Robbert J de Winter12,
  17. Moniek P M de Maat13,
  18. Olga A Iakoubova14,
  19. Naveed Sattar15,
  20. Jim Shepherd16,
  21. Rudi G J Westendorp4,
  22. J Wouter Jukema1,2,3,17
  23. also on behalf of the PROSPER, WOSCOPS and GENDER study groups*
  1. 1Department of Cardiology, Leiden University Medical Center, RC Leiden, The Netherlands
  2. 2Interuniversity Cardiology Institute of the Netherlands (ICIN), Utrecht, The Netherlands
  3. 3Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
  4. 4Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
  7. 7Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
  8. 8Molecular Epidemiology Section, Leiden University Medical Center, Leiden, The Netherlands
  9. 9Department of Medical Statistics, Academic Medical Center, Amsterdam, The Netherlands
  10. 10Department of Cardiology, University Medical Center, Utrecht, The Netherlands
  11. 11Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands
  12. 12Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
  13. 13Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
  14. 14Celera, Inc, Alameda, California, USA
  15. 15BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, Scotland, UK
  16. 16Department of Vascular Biochemistry, University of Glasgow, Scotland, UK
  17. 17Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
  1. Correspondence to Professor J Wouter Jukema, Leiden University Medical Center, Department of Cardiology, C5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands; j.w.jukema{at}lumc.nl

Abstract

Aims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality.

Methods and results The association of genetic variation in the PCAF-gene with CHD, restenosis and mortality was investigated in three large cohorts. The results were combined to examine overall effects on CHD mortality and on restenosis risk. Compared with the homozygous −2481G allele in the PCAF promoter, a significant reduction in CHD mortality risk with the homozygous −2481C PCAF promoter allele was observed. A combined risk reduction for CHD death for the three studies was 21% (15–26%; p=8.1×10–4). In elderly patients (>58 years) the effects were stronger. Furthermore, this PCAF allele was significantly associated with all-cause mortality (p=0.001). Functional analysis showed that nuclear factors interact in vitro with the oligonucleotides encompassing the −2481G/C polymorphism and that this interaction might be influenced by this polymorphism in the PCAF promoter. Moreover, modulation of PCAF gene expression was detectable upon cuff-placement in an animal model of reactive stenosis.

Conclusion We showed in three large prospective studies that the −2481C allele in the PCAF promoter is associated with a significant survival advantage in elderly patients. Our observations promote the concept that epigenetic processes are under genetic control and that, other than environment, variation in genes encoding KATs may also determine susceptibility to CHD outcomes and mortality.

  • Coronary artery disease
  • coronary heart disease
  • epigenetics
  • genetics
  • histone acetylation
  • P300/CBP associated factor
  • restenosis

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Footnotes

  • * The PROSPER study group Scotland—J Shepherd, CJ Packard, A Gaw (Department of Pathological Biochemistry, University of Glasgow); PW Macfarlane, DJ Stott (Division of Cardiovascular and Medical Sciences, University of Glasgow); I Ford (Robertson Centre for Biostatistics, University of Glasgow); Ireland—MB Murphy, BM Buckley (Department of Pharmacology and Therapeutics, University College Cork); IJ Perry (Department of Epidemiology and Public Health, University College Cork); M Hyland, C Twomey (Department of Geriatric Medicine, Cork University Hospital); BJ Sweeney (Department of Neurology, Cork University Hospital); The Netherlands—S Trompet, GJ Blauw, AJM de Craen, RGJ Westendorp (Section of Gerontology and Geriatrics, Leiden University Medical Center); ELEM Bollen (Department of Neurology, Leiden University Medical Center); JW Jukema (Department of Cardiology, Leiden University Medical Center).

    The WOSCOPS study group Scotland—J Shepherd, CJ Packard (Department of Pathological Biochemistry, University of Glasgow); SM Cobbe, AR Lorimer, PW Macfarlane (Department of Medical Cardiology); JH McKillop (Department of Medicine); I Ford (Roberston Centre for Biostatistics) from the University of Glasgow, Glasgow and CG Isles (Department of Medicine) from the Dumfries and Galloway District General Hospital, Dumfries.

    The GENDER study group The Netherlands—JW Jukema, D Pons, PS Monraats, A van der Laarse, EE van der Wall (Department of Cardiology, Leiden University Medical Center); RR Frants (Department of Human Genetics, Leiden University Medical Center); MPM de Maat (Department of Hematology, Erasmus University Medical Center, Rotterdam); AH Zwinderman (Department of Medical Statistics, Academic Medical Center, Amsterdam); PAFM Doevendans (Department of Cardiology, University Medical Center, Utrecht); RA Tio (Department of Cardiology, University Medical Center Groningen); RJ de Winter (Department of Cardiology, Academic Medical Center, Amsterdam); J Waltenberger (Department of Cardiology, Academic Hospital Maastricht).

  • Funding This study was supported by grants from the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands (ICIN), the Macropa Foundation, the Center for Medical Systems Biology (CMSB), a centre of excellence approved by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NWO), and the EU Project HEALTH-F2-2007 223004 PHASE.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The protocols meet the criteria of the Declaration of Helsinki and were approved by the medical ethics committees of each participating institution.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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