Accelerated decline in lung function in cigarette smokers is associated with TP53/MDM2 polymorphisms.
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.
Hancox
Robert J
RJ
Dunedin Multidisciplinary Health and Development Research Unit, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Poulton
Richie
R
Welch
David
D
Olova
Nelly
N
McLachlan
Christene R
CR
Greene
Justina M
JM
Sears
Malcolm R
MR
Caspi
Avshalom
A
Moffitt
Terrie E
TE
Robertson
Stephen P
SP
Braithwaite
Antony W
AW
D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D015331:Cohort Studies; D004249:DNA Damage; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2