Research Decreased PM10 Exposure Attenuates Age-Related Lung Function Genetic Variants in p53, p21, and CCND1 Modify This Effect Decline: Medea Imboden,1,2 Joel Schwartz,3 Christian Schindler,4 Ivan Curjuric,1,4 Wolfgang Berger,2 Sally L.J. Liu,4 Erich W. Russi,5 Ursula Ackermann-Liebrich,4 Thierry Rochat,6 Nicole M. Probst-Hensch,1 and the SAPALDIA Team 1Department of Chronic Disease Epidemiology, Institute of Social and Preventive Medicine, and 2Institute of Medical Genetics, University of Zurich, Zurich, Switzerland; 3Department of Environmental Health, Harvard School of Public Health, Boston, Massachussetts, USA; 4Institute of Social and Preventive Medicine, University of Basel, Basel, Switzerland; 5Department of Pneumology, University Hospital Zurich, Zurich, Switzerland; 6Division of Pulmonary Medicine, University Hospitals Geneva, Geneva, Switzerland Background : Decreasing exposure to airborne particulates was previously associated with reduced age-related decline in lung function. However, whether the benefit from improved air quality depends on genetic background is not known. Recent evidence points to the involvement of the genes p53 and p21 and of the cell cycle control gene cyclin D1 (CCND1) in the response of bron- chial cells to air pollution. Methods o Bjectiv : We determined in 4,326 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) whether four single-nucleotide polymorphisms in three genes [CCND1 (rs9344 [P242P], rs667515), p53 (rs1042522 [R72P]), and p21 (rs1801270 [S31R])] modified the previously observed attenuation of the decline in the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF25–75) associated with improved air quality. : Subjects of the prospective population-based SAPALDIA cohort were assessed in 1991 and 2002 by spirometry, questionnaires, and biological sample collection for genotyping. We assigned spatially resolved concentrations of particulate matter with aerodynamic diameter ≤ 10 µm (PM10) to each participant’s residential history 12 months before the baseline and follow-up assessments. r esult : The effect of diminishing PM10 exposure on FEF25–75 decline appeared to be modified by p53 R72P, CCND1 P242P, and CCND1 rs667515. For example, a 10-µg/m3 decline in aver- age PM10 exposure over an 11-year period attenuated the average annual decline in FEF25–75 by 21.33 mL/year (95% confidence interval, 10.57–32.08) among participants homozygous for the CCND1 (P242P) GG genotype, by 13.72 mL/year (5.38–22.06) among GA genotypes, and by 6.00 mL/year (–4.54 to 16.54) among AA genotypes. c onclusi : Our results suggest that cell cycle control genes may modify the degree to which improved air quality may benefit respiratory function in adults. k ey words : air pollution, cell cycle, cohort study, genes, respiratory function tests. Environ Health Perspect 117:1420–1427 (2009). doi:10.1289/ehp.0800430 available via http://dx.doi.org/ [Online 26 May 2009] The tumor suppressor p53, a nuclear tran- scription factor, binds to response elements in the promoter region of many genes and plays a pivotal role in apoptosis. It induces up- regulation of the expression of many pro- apoptotic genes and down-regulation of anti- apoptotic genes (Oren et al. 2002). CCND1 (cyclin D1) is known to promote cell prolif- eration through cell cycle G1–S phase transi- tion. The protein p21 (also known as Waf1 or Cip1) is a direct functional counterpart of CCND1 and an important downstream effector of p53 action that negatively regulates cell proliferation. CCND1, p21, and p53 all harbor polymorphisms of hypothesized func- tional relevance that have been extensively studied in the context of cancer (Choi et al. 2008; Lu et al. 2008; Zhou et al. 2007). In this study, we examined whether these poly- morphisms modified the degree to which the Address correspondence to N.M. Probst-Hensch, Department of Chronic Disease Epidemiology, Institute of Social and Preventive Medicine, Sumatrastrasse 30, CH-8006 Zurich, Switzerland. Telephone: 41-44-634-53-73. Fax: 41-44-634- 40-09. E-mail: Nicole.Probst@ifspm.uzh.ch Supplemental Material is available online (doi:10.1289/ehp.0800430.S1 via http://dx.doi.org/) The study could not have been done without the help of the study participants, technical and adminis- trative support, and the medical teams and fieldworkers at the local study sites: local field-workers M. Broglie, M. Bünter, D. Gashi (Aarau); R. Armbruster, T. Damm, U. Egermann, M. Gut, L. Maier, A. Vögelin, L. Walter (Basel); D. Jud, N. Lutz (Davos); M. Ares, M. Bennour, B. Galobardes, E. Namer (Geneva); B. Baumberger, S. Boccia Soldati, E. Gehrig-Van Essen, S. Ronchetto (Lugano); C. Bonvin, C. Burrus (Montana); S. Blanc, A.V. Ebinger, M.L. Fragnière, J. Jordan (Payerne); and R. Gimmi, N. Kourkoulos, U. Schafroth (Wald); and administrative staff N. Bauer, D. Baehler, C. Gabriel, and R. Nilly. Research support was provided by the Swiss National Science Foundation (grants 4026-28099, 3347CO- 108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 32-65896.01, 32-59302.99, 32-52720.97, and 32-4253.94); Swiss Federal Office for Forest, Environment, and Landscape; Swiss Federal Office of Public Health; Swiss Federal Office of Roads and Transport; canton governments of Aargau, Basel- Stadt, Basel-Land, Geneva, Luzern, Ticino, and Zurich; Swiss Lung League; canton’s Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino, and Zurich; and the Walter-Honegger Foundation. The authors declare they have no competing finan- cial interests. Received 27 November 2008; accepted 26 May 2009. ovlume 117 | number 9 | September 2009 • Environmental Health Perspectives A large body of evidence underscores the adverse effect of long-term exposure to ambi- ent particulate matter (PM) air pollution on respiratory health (Brunekreef and Forsberg 2005; Gotschi et al. 2008). Among adults in Switzerland, we have previously demon- strated cross-sectionally that residents of more polluted areas have lower lung func- tion (Ackermann-Liebrich et al. 1997). More recently, we presented evidence from the same population-based cohort [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA)] that decreasing exposure to airborne PM attenu- ated the average age-related decline in lung function. The associations were strongest for respiratory function tests reflecting small- airway function, namely, FEF25–75 [forced expiratory flow between 25% and 75% of forced vital capacity (FVC)] (Downs et al. 2007). Similar results from studies follow- ing interventions such as building bypasses for congested traffic routes (Burr et al. 2004; Hedley et al. 2002) or banning environmen- tal tobacco smoke (ETS) exposure (Goodman et al. 2007; Menzies et al. 2006) showed that 1420 the improvements in air quality were accom- panied by a decrease in cardiopulmonary mortality and an improvement in respiratory symptoms and lung function. However, it is still unknown whether all subjects benefit equally from a reduction in air pollution. Variation in genes mediating the patho- biological effect of air pollution in the lung may codetermine the degree to which a person benefits from better air quality. Experimental evidence indicates that PM alters expression of tumor protein gene p53, cyclin-dependent kinase inhibitor 1A gene (p21), and the cyclin D1 gene (CCND1) and subsequently affects cell proliferation and apoptosis of lung fibro- blasts, lymphocytes, and alveolar epithelial cells (Bayram et al. 2006; Dagher et al. 2006; Nyunoya et al. 2006; Rosas Perez et al. 2007; Soberanes et al. 2006). PM is furthermore well known to induce oxidative stress in the airways (Li et al. 2008). In fact, the expres- sion of all three gene candidates, p53, p21, and CCND1, in bronchial epithelial cells and lung fibroblasts seems to be regulated in part by redox-dependent mechanisms (Jiao et al. 2008; Ranjan et al. 2006; Yao et al. 2008).