p53, CCND1, and p21 variants modify PM10 effect models. Although p53 and p21 expression has been consistently shown to be increased upon PM exposure (Bayram et al. 2006; Dagher et al. 2006; Jiao et al. 2008; Nyunoya et al. 2006; Palozza et al. 2006; Rosas Perez et al. 2007; Soberanes et al. 2006; Yao et al. 2008; Zhang et al. 2007), CCND1 expres- sion has been reported to be either inhib- ited (via p21 activation) (Palozza et al. 2006; Zhang et al. 2007) or increased [p53-driven N-terminal C-Jun kinase (cJUN) activation] (Bayram et al. 2006; Dagher et al. 2007; Jiao et al. 2008). Such variations in the expres- sion of cell cycle genes mediate the adaptive cellular response to changes in environmen- tal exposure. They might well be the starting point of PM10-induced pathologic changes in morphology and in the type and number of lung fibroblasts and bronchial epithelial cells. Activation of cell proliferation processes may help to maintain intact airways even in the presence of environmental toxins, as sug- gested by genetic ablation of p21 in mice, which conferred protection against cigarette- smoke–induced lung inflammation and injury (Yao et al. 2008). Aspects of bronchial tissue remodeling represent key features of patho- logic changes in the etiology of most airway disorders. However, how proliferation and apoptosis relate to airway remodeling in gen- eral remains poorly understood and is likely to be disease specific. Three of the four polymorphisms investi- gated here have been studied before, mainly in cancer studies, and allelic functional dif- ferences have been proposed. The functional consequence of p53 R72P polymorphism was studied in detail. The Arg72-allele (G-allele) of p53 is more active at inducing apoptosis than is the p53 Pro72-allele. In fact, Pro72 is part of a PXXP motif known to be critical in binding of a p53-specific inhibitory protein, iASPP (inhibitory member of the apoptosis- stimulating protein phosphatase family) (Bergamaschi et al. 2006). Along the line of the proposed functional consequence of this genetic variant, meta-analysis results have recently shown that the homozygous Pro/Pro genotype showed a proproliferative effect and was associated with increased gastric cancer risk (Zhou et al. 2007). In our association study, we observed the most pronounced benefits of ΔPM10 with regard to FEF25–75 decline in subjects with one or two Arg72- alleles, which are expected to induce apop- tosis more potently than the Pro72-allele. In contrast, homozygous carriers of the Pro72- allele did not appear to benefit from the improvement in air quality. The functional studies of the common CCND1 polymorphism P242P showed a modification of the alternative splicing events in exon 4 because the G-to-A substitution alters the consensus sequence of the splicing donor site (Betticher et al. 1995; Howe and Lynas 2001). As recently reported by three meta-analyses, the homozygous AA genotype was associated with increased risk of various types of cancer (Lu et al. 2008; Pabalan et al. 2008; Tan et al. 2008). The A-allele of the CCND1 870G>A (P242P) polymorphism, a proposed genetic risk factor for lung can- cer, was previously associated with impaired cell cycle regulation and accumulation of DNA damage in the airway (Buch et al. 2005; Munnia et al. 2006). In our association analy- sis, we observed that homo- or heterozygous G-allele carriers benefited more from the decrease in PM10 exposure than did homozy- gous A-allele carriers. The association of the second CCND1 (–7006G>C) SNP with can- cer or any other outcome has not been investi- gated previously. Its functional consequence, if any, might be regulatory because it is situated upstream of the CCND1 gene. But it is also possible that this SNP is in high linkage with a yet unknown functional CCND1 variant, just as it is also in high LD with the CCND1 P242P variant. The polymorphism S31R in the p21 gene was shown to be located in the DNA-binding zinc finger motif and thus has been thought to alter the function of the p21 protein (Lukas et al. 1997). However, results of cancer stud- ies for this SNP have been inconsistent with regard to the size and direction of relative risk estimates (Choi et al. 2008), and we observed no interaction between this SNP and ΔPM10 on lung function decline. Thus, the cancer-promoting p53 and CCND1 alleles seem to reduce the benefit of improved air quality on respiratory func- tion. Only limited epidemiological data exist on the association of p53, p21, or CCND1 SNPs with respiratory diseases such as asthma, emphysema, and chronic obstructive pulmo- nary disease (COPD). The polymorphisms we evaluated in p53 and p21 have previously been associated with smoking-related COPD. Compared with healthy smokers, the cancer risk allele of p53 (Pro72-allele), and the p21 Arg31-allele were overrepresented in COPD patients (Lee et al. 2006). The extrapola- tion of observed associations with cancer to expected associations with lung function is not straightforward. The present findings and our interpretation of them should be consid- ered as exploratory in nature and need con- firmation in independent studies. The relative impacts of cell proliferation and apoptosis on different cell types in the lung and on respira- tory function must be further investigated by experimental studies. The strengths of the present study are its prospective design, its rather large sam- ple size, and detailed characterization of the study participants, as well as the availability of individual air pollution exposure history since 1990. We were thus able to adjust lung function decline for most of the potential con- founders. Nonetheless, information on some relevant confounders such as dietary antioxi- dant intake and physical activity was collected only at follow-up. Lacking data on the degree of genetic admixture of the Swiss general popu- lation is an additional drawback. However, we expect little bias due to genetic admix- ture, because the prevalence of several poly- morphisms studied in the cohort did not vary across the three major Swiss language groups. We assessed a very limited number of carefully selected candidate polymorphisms; for some of the SNPs and haplotypes, and especially for the Appendix 1. The SAPALDIA Team. Member Specialty Study directorate U. Ackermann-Liebrich Epidemiology J.M. Gaspoz Cardiology P. Leuenberger Pneumology L.J.S. Liu Exposure N.M. Probst Hensch Epidemiology/genetic and molecular biology C. Schindler Statistics T. Rochat Pneumology Scientific team J.C. Barthélémy Cardiology W. Berger Genetic and molecular biology R. Bettschart Pneumology A. Bircher Allergology G. Bolognini Pneumology O. Brändli Pneumology M. Brutsche Pneumology L. Burdet Pneumology M. Frey Pneumology M.W. Gerbase Pneumology D. Gold Epidemiology/cardiology/ pneumology W. Karrer Pneumology R. Keller Pneumology B. Knöpfli Pneumology N. Künzli Epidemiology/exposure U. Neu Exposure L. Nicod Pneumology M. Pons Pneumology E. Russi Pneumology P. Schmid-Grendelmeyer Allergology J. Schwartz Epidemiology P. Straehl Exposure J.M. Tschopp Pneumology A. von Eckardstein Clinical chemistry J.P. Zellweger Pneumology E. Zemp Stutz Epidemiology Scientific team at coordinating centers P.O. Bridevaux Pneumology I. Curjuric Epidemiology J. Dratva Epidemiology D. Felber Dietrich Cardiology D. Keidel Statistics M. Imboden Genetic and molecular biology H. Phuleria Exposure E. Schaffner Statistics G.A. Thun Genetic and molecular biology Environmental Health Perspectives • volume 117 | number 9 | September 2009 1425