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Human Genetics

, 126:559 | Cite as

Accelerated decline in lung function in cigarette smokers is associated with TP53/MDM2 polymorphisms

  • Robert J. Hancox
  • Richie Poulton
  • David Welch
  • Nelly Olova
  • Christene R. McLachlan
  • Justina M. Greene
  • Malcolm R. Sears
  • Avshalom Caspi
  • Terrie E. Moffitt
  • Stephen P. Robertson
  • Antony W. BraithwaiteEmail author
Original Investigation

Abstract

In vitro studies have shown that p53 mediates a protective response against DNA damage by causing either cell-cycle arrest and DNA repair, or apoptosis. These responses have not yet been demonstrated in humans. A common source of DNA damage in humans is cigarette smoke, which should activate p53 repair mechanisms. As the level of p53 is regulated by MDM2, which targets p53 for degradation, the G-allele of a polymorphism in intron 1 of MDM2 (rs2279744:G/T), that results in higher MDM2 levels, should be associated with a reduced p53 response and hence more DNA damage and corresponding tissue destruction. Similarly, the alleles of rs1042522 in TP53 that encode arginine (G-allele) or proline (C-allele) at codon 72, which cause increased pro-apoptotic (G-allele) or cell-cycle arrest activities (C-allele), respectively, may moderate p53’s ability to prevent DNA damage. To test these hypotheses, we examined lung function in relation to cumulative history of smoking in a population-based cohort. The G-alleles in MDM2 and TP53 were found to be associated with accelerated smoking-related decline in lung function. These data support the hypothesis that p53 protects from DNA damage in humans and provides a potential explanation for the variation in lung function impairment amongst smokers.

Keywords

Lung Function Risk Allele Cigarette Smoke Exposure Lung Function Decline TP53 Polymorphism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was supported by the Health Research Council of New Zealand (03/27); Dunedin School of Medicine Strategic Research Initiative Grant; the US National Institute of Mental Health (grants MH45070, MH49414 and MH077874), and the UK Medical Research Council (G0100527). DNA collection and extraction was funded by the University of Wisconsin. Dr. Sears holds the AstraZeneca Chair in Respiratory Epidemiology at McMaster University. Avshalom Caspi holds a Royal Society Wolfson Merit Award. Professor Braithwaite is a Cancer Institute NSW Programme Leader. We are grateful to the Study members and their parents for their continued support. We also thank Dr. Phil A. Silva, the study founder. Mr. T. Manley is thanked for assistance with the genotyping. The authors have no conflicting financial interests.

These studies were carried out according to current New Zealand standards with ethical approval and informed individual consents.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Robert J. Hancox
    • 1
  • Richie Poulton
    • 1
  • David Welch
    • 1
  • Nelly Olova
    • 2
  • Christene R. McLachlan
    • 1
  • Justina M. Greene
    • 3
  • Malcolm R. Sears
    • 3
  • Avshalom Caspi
    • 4
    • 5
  • Terrie E. Moffitt
    • 4
    • 5
  • Stephen P. Robertson
    • 2
  • Antony W. Braithwaite
    • 6
    • 7
    Email author
  1. 1.Dunedin Multidisciplinary Health and Development Research Unit, Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand
  2. 2.Department of Women’s and Children’s Health, Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand
  3. 3.Firestone Institute for Respiratory HealthMcMaster University Faculty of Health Sciences and St Joseph’s HealthcareHamiltonCanada
  4. 4.Departments of Psychology & Neuroscience and Psychiatry & Behavioural Sciences, Institute for Genome Sciences and PolicyDuke UniversityDurhamUSA
  5. 5.MRC Social, Genetic, and Developmental Psychiatry CentreInstitute of Psychiatry, King’s CollegeLondonUK
  6. 6.Department of Pathology, Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand
  7. 7.Children’s Medical Research InstituteThe University of SydneySydneyAustralia

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