Imboden et al. p21 SNP and CCND1 haplotype 4, statistical power to detect effect estimation was very lim- ited. A more comprehensive assessment of gene variants in the apoptosis pathway and genes regulating apoptosis in lung tissue needs to be addressed in future larger studies. Nevertheless, even for the small number of genetic vari- ants investigated, multiple testing represents a limitation in the interpretation of the present results. Consistency of the associations across genes involved in cell cycle control, as well as across various lung function outcomes, dimin- ishes the likelihood of chance findings, as does the strength of the observed pint values. Finally, participation at follow-up and in this present study was not complete, so partici- pation bias cannot be excluded. However, because we observed comparable results in all subjects and in never-smokers and in the absence of different effects between men and women, the lower participation rate in men and smokers is not likely to have caused bias. In conclusion, our results suggest that even at low to moderate levels of air pollu- tion, such as in Switzerland, some but not all persons benefit from improved air quality. Given the novelty of the finding and the limi- tations inherent to this study, the results need independent confirmation. Future studies must address additional issues. First, gene variants relevant to cell cycle control must be studied more comprehensively. Second, it is of interest to know whether this novel candidate pathway might determine susceptibility to both improvements and declines in air quality. Ref Rencs Ackermann-Liebrich U, Kuna-Dibbert B, Probst-Hensch N, Schindler C, Felber Dietrich D, Zemp Stutz E, et al. 2005. Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991–2003: methods and characterization of participants. Soz Praventiv Med 50:245–263. Ackermann-Liebrich U, Leuenberger P, Schwartz J, Schindler C, Monn C, Bolognini G, et al. 1997. Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Am J Respir Crit Care Med 155(1):122–129. American Thoracic Society. 1995. Standardization of spirometry, 1994 Update. Am J Respir Crit Care Med 152(3):1107–1136. Bayram H, Ito K, Issa R, Ito M, Sukkar M, Chung KF. 2006. Regulation of human lung epithelial cell numbers by diesel exhaust particles. Eur Respir J 27(4):705–713. Behndig AF, Mudway IS, Brown JL, Stenfors N, Helleday R, Duggan ST, et al. 2006. Airway antioxidant and inflam- matory responses to diesel exhaust exposure in healthy humans. Eur Respir J 27(2):359–365. Bergamaschi D, Samuels Y, Sullivan A, Zvelebil M, Breyssens H, Bisso A, et al. 2006. iASPP preferentially binds p53 proline- rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet 38(10):1133–1141. Betticher DC, Thatcher N, Altermatt HJ, Hoban P, Ryder WD, Heighway J. 1995. Alternate splicing produces a novel cyclin D1 transcript. Oncogene 11(5):1005–1011. Bosson J, Barath S, Pourazar J, Behndig AF, Sandstrom T, Blomberg A, et al. 2008. Diesel exhaust exposure enhances the ozone induced airway inflammation in healthy humans. Eur Respir J 31(6):1234–1240. Brunekreef B, Forsberg B. 2005. Epidemiological evidence of effects of coarse airborne particles on health. Eur Respir J 26(2):309–318. 1426 ovlume 117 | number 9 | September 2009 • Environmental Health Perspectives Buch S, Zhu B, Davis AG, Odom D, Siegfried JM, Grandis JR, et al. 2005. Association of polymorphisms in the cyclin D1 and XPD genes and susceptibility to cancers of the upper aero-digestive tract. Mol Carcinog 42(4):222–228. Burney PG, Luczynska C, Chinn S, Jarvis D. 1994. The European spirometers—a challenge in lung function follow-up studies. Swiss Med Wkly 135(33–34):503–508. Lee YL, Chen W, Tsai WK, Lee JC, Chiou HL, Shih CM, et al. 2006. Polymorphisms of p53 and p21 genes in chronic obstructive pulmonary disease. J Lab Clin Med 147(5):228–233. Community Respiratory Health Survey. Eur Respir J Li N, Xia T, Nel AE. 2008. The role of oxidative stress in ambient 7(5):954–960. 61(3):212–218. Burr ML, Karani G, Davies B, Holmes BA, Williams KL. 2004. Effects on respiratory health of a reduction in air pollu- tion from vehicle exhaust emissions. Occup Environ Med Ceschi M, Sun CL, Van Den Berg D, Koh WP, Yu MC, Probst- Hensch N. 2005. The effect of cyclin D1 (CCND1) G870A- polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore. Carcinogenesis 26(8):1457–1464. Choi YY, Kang HK, Choi JE, Jang JS, Kim EJ, Cha SI, et al. 2008. Comprehensive assessment of P21 polymorphisms and lung cancer risk. J Hum Genet 53(1):87–95. particulate matter-induced lung diseases and its implica- tions in the toxicity of engineered nanoparticles. Free Radic Biol Med 44(9):1689–1699. Li XY, Gilmour PS, Donaldson K, MacNee W. 1996. Free radical activity and pro-inflammatory effects of particulate air pol- lution (PM10) in vivo and in vitro. Thorax 51(12):1216–1222. Li XY, Gilmour PS, Donaldson K, MacNee W. 1997. In vivo and in vitro proinflammatory effects of particulate air pollution (PM10). Environ Health Perspect 105(suppl 5):1279–1283. Liu LJ, Curjuric I, Keidel D, Heldstab J, Künzli N, Bayer-Oglesby L, et al. 2007. Characterization of source-specific air pollu- tion exposure for a large population-based Swiss cohort (SAPALDIA). Environ Health Perspect 115:1638–1645. Dagher Z, Garcon G, Billet S, Gosset P, Ledoux F, Courcot D, Lu C, Dong J, Ma H, Jin G, Hu Z, Peng Y, et al. 2008. CCND1 et al. 2006. Activation of different pathways of apoptosis by air pollution particulate matter (PM2.5) in human epithelial lung cells (L132) in culture. Toxicology 225(1):12–24. G870A polymorphism contributes to breast cancer sus- ceptibility: a meta-analysis. Breast Cancer Res Treat 116(3):571-575. Dagher Z, Garcon G, Billet S, Verdin A, Ledoux F, Courcot D, Lukas J, Groshen S, Saffari B, Niu N, Reles A, Wen WH, et al. et al. 2007. Role of nuclear factor-kappa B activation in the adverse effects induced by air pollution particulate matter (PM2.5) in human epithelial lung cells (L132) in culture. J Appl Toxicol 27(3):284–290. Donaldson K, Stone V, Borm PJ, Jimenez LA, Gilmour PS, Schins RP, et al. 2003. Oxidative stress and calcium sig- naling in the adverse effects of environmental particles (PM10). Free Radic Biol Med 34(11):1369–1382. 1997. WAF1/Cip1 gene polymorphism and expression in carcinomas of the breast, ovary, and endometrium. Am J Pathol 150(1):167–175. Martin BW, Ackermann-Liebrich U, Leuenberger P, Künzli N, Stutz EZ, Keller R, et al. 1997. SAPALDIA: methods and participation in the cross-sectional part of the Swiss Study on Air Pollution and Lung Diseases in Adults. Soz Praventivmed 42(2):67–84. Downs S, Brandli O, Zellweger JP, Schindler C, Künzli N, Menzies D, Nair A, Williamson PA, Schembri S, Al-Khairalla MZ, Gerbase M, et al. 2005. Accelerated decline in lung function in smoking women with airway obstruction: SAPALDIA 2 cohort study Respir Res 6(1):45; doi:10.1186/1465-9921-6-45 [Online 26 May 2005]. Barnes M, et al. 2006. Respiratory symptoms, pulmonary function, and markers of inflammation among bar workers before and after a legislative ban on smoking in public places. JAMA 296(14):1742–1748. Downs SH, Schindler C, Liu LJ, Keidel D, Bayer-Oglesby L, Morrison D, Rahman I, Lannan S, MacNee W. 1999. Epithelial per- Brutsche MH, et al. 2007. Reduced exposure to PM10 and attenuated age-related decline in lung function. N Engl J Med 357(23):2338–2347. Goodman P, Agnew M, McCaffrey M, Paul G, Clancy L. 2007. Effects of the Irish smoking ban on respiratory health of bar workers and air quality in Dublin pubs. Am J Respir Crit Care Med 175(8):840–845. Gotschi T, Heinrich J, Sunyer J, Künzli N. 2008. Long-term effects of ambient air pollution on lung function: a review. Epidemiology 19(5):690–701. 41(9):1499–1505. meability, inflammation, and oxidant stress in the air spaces of smokers. Am J Respir Crit Care Med 159(2):473–479. Munnia A, Bonassi S, Verna A, Quaglia R, Pelucco D, Ceppi M, et al. 2006. Bronchial malondialdehyde DNA adducts, tobacco smoking, and lung cancer. Free Radic Biol Med Nightingale JA, Maggs R, Cullinan P, Donnelly LE, Rogers DF, Kinnersley R, et al. 2000. Airway inflammation after con- trolled exposure to diesel exhaust particulates. Am J Respir Crit Care Med 162(1):161–166. Hedley AJ, Wong CM, Thach TQ, Ma S, Lam TH, Anderson HR. Nyunoya T, Monick MM, Klingelhutz A, Yarovinsky TO, 2002. Cardiorespiratory and all-cause mortality after restrictions on sulphur content of fuel in Hong Kong: an intervention study. Lancet 360(9346):1646–1652. Cagley JR, Hunninghake GW. 2006. Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol 35(6):681–688. Howe D, Lynas C. 2001. The cyclin D1 alternative transcripts [a] Oren M, Damalas A, Gottlieb T, Michael D, Taplick J, Leal JF, Künzli N, Ackermann-Liebrich U, Keller R, Perruchoud AP, Rahman I, Gilmour PS, Jimenez LA, MacNee W. 2002. Oxidative and [b] are expressed in normal and malignant lympho- cytes and their relative levels are influenced by the poly- morphism at codon 241. Haematologica 86(6):563–569. Imboden M, Downs SH, Senn O, Matyas G, Brandli O, Russi EW, et al. 2007. Glutathione S-transferase genotypes modify lung function decline in the general population: SAPALDIA cohort study. Respir Res 8:2.; doi:10.1186/1465-9921-8-2 [Online 11 January 2007]. Jiao S, Liu B, Gao A, Ye M, Jia X, Zhang F, et al. 2008. Benzo(a) pyrene-caused increased G(1)-S transition requires the activation of c-Jun through p53-dependent PI-3K/Akt/ERK pathway in human embryo lung fibroblasts. Toxicol Lett 178(3):167–175. Künzli N, Ackermann-Liebrich U, Brandli O, Tschopp JM, Schindler C, Leuenberger P. 2000a. Clinically “small” effects of air pollution on FVC have a large public health impact. Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) team. Eur Respir J 15(1):131–136. 356(9232):795–801. Schindler C. 1995. Variability of FVC and FEV1 due to tech- nician, team, device and subject in an eight centre study: three quality control studies in SAPALDIA. Swiss Study on Air Pollution and Lung Disease in Adults. Eur Respir J 8(3):371–376. Künzli N, Kaiser R, Medina S, Studnicka M, Chanel O, Filliger P, et al. 2000b. Public-health impact of outdoor and traffic- related air pollution: a European assessment. Lancet Künzli N, Kuna-Dibbert B, Keidel D, Keller R, Brändli O, Schindler C, et al. 2005. Longitudinal validity of et al. 2002. Regulation of p53: intricate loops and delicate balances. Biochem Pharmacol 64(5–6):865–871. Pabalan N, Bapat B, Sung L, Jarjanazi H, Francisco-Pabalan O, Ozcelik H. 2008. Cyclin D1 Pro241Pro (CCND1-G870A) poly- morphism is associated with increased cancer risk in human populations: a meta-analysis. Cancer Epidemiol Biomarkers Prev 17(10):2773–2781. Palozza P, Serini S, Curro D, Calviello G, Igarashi K, Mancuso C. 2006. beta-Carotene and cigarette smoke condensate regulate heme oxygenase-1 and its repressor factor Bach1: relationship with cell growth. Antioxid Redox Signal 8(5–6):1069–1080. Probst-Hensch NM, Sun CL, Van Den Berg D, Ceschi M, Koh WP, Yu MC. 2006. The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothio- cyanate intake in the Singapore Chinese Health Study. Carcinogenesis 27(12):2475–2482. stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: poten- tial mechanism in gene transcription in lung inflammation. Mol Cell Biochem 234–235(1–2):239–248. Ranjan P, Anathy V, Burch PM, Weirather K, Lambeth JD, Heintz NH. 2006. Redox-dependent expression of cyclin D1 and cell proliferation by Nox1 in mouse lung epithelial cells. Antioxid Redox Signal 8(9–10):1447–1459. Rosas Perez I, Serrano J, Alfaro-Moreno E, Baumgardner D, Garcia-Cuellar C, Martin Del Campo JM, et al. 2007. Relations between PM10 composition and cell toxicity: