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.
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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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Christene R. McLachlan is deceased.
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Hancox, R.J., Poulton, R., Welch, D. et al. Accelerated decline in lung function in cigarette smokers is associated with TP53/MDM2 polymorphisms. Hum Genet 126, 559–565 (2009). https://doi.org/10.1007/s00439-009-0704-z
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DOI: https://doi.org/10.1007/s00439-009-0704-z