Imboden et al. pint = 0.024 GGGC CC CA/AA CC pint = 0.017 GG GAAA pint = 0.006 CC GGGC p53 Pro72Arg p21Ser31Arg CCND1 P242P CCND1-7006G>C p53 Pro72Arg p21Ser31Arg CCND1 P242P CCND1-7006G>C Figure 1. Attenuation of average annual FEF25–75 decline associated with a 10-µg/m3 decrease in average home outdoor PM10 exposure between 1991 and 2002, by genotype status, in all study participants (A) and in never-smokers only (B). A positive value for FEF25–75 on the y-axes represents the average attenuation in lung function decline associated with an average 10-µg/m3 PM10 decrease during follow-up period. Bonferroni significance level for four comparisons p = 0.013. Table 2. Effect modification by genotypes: associationa of change in average home outdoor PM10 (per decrease of 10 µg/m3 between 1991 and 2002) with average annual decline in FEF25–75 (mL/year), by geno- type status. aCovariates were age, age2, sex, height, parental smoking, sine and cosine function of day of examination to control for seasonal effects, level of education at SAPALDIA1, change in level of education, Swiss nationality, self-reported occupa- tional exposure to dust and occupational exposure to fumes at SAPALDIA1 and SAPALDIA2 (yes/no), smoking status at SAPALDIA2 (never, former, or current), pack-years up to SAPALDIA1, pack-years between SAPALDIA1 and -2, cigarettes per day at SAPALDIA1 and -2, atopy, BMI at SAPALDIA1, change in BMI, interaction between the two BMI variables, and baseline PM10 exposure. bPositive estimates indicate attenuation of lung function decline associated with PM10 decrease. Negative estimates indicate acceleration of lung function decline with PM10 decrease. cp-Value for interaction between change in home outdoor exposure of PM10 and genotype parameterized in three different genetic models. The pint values presented here represent the most significant (lowest) p-value obtained from the three different genetic mod- els. Bonferroni significance level for 12 comparisons [three respiratory function tests (FVC, FEV1, FEF25–75) × times four association tests], p = 0.00417. dGenotype distribution: p21 CA, n = 594; p21 AA, n = 31. eDiplotype distribution is labeled as follows: –/–, none of the specific haplotype present; (rs667515, rs9344)/– (e.g., GG/–), one of the specific haplotypes pres- ent; (rs667515, rs9344)/(rs667515, rs9344) (e.g., GG/GG), for two of the specific haplotypes present. 1424 ovlume 117 | number 9 | September 2009 • Environmental Health Perspectives pint = 0.015 ) ra50 e /Ly30 GGGC (m10 5 5– 7 0 2 FE–20 F CC CA/AA CC pint = 0.033 GG GA AA pint = 0.041 CC GG GC No. 2,407 1,637 282 3,701 625 1,211 2,140 975 1,628 2,058 640 3,125 1,088 113 1,251 2,150 925 1,678 2,048 600 4,239 84 3 Average annual FEF25–75 declineb 17.37 11.63 –4.33 12.72 23.88 21.33 13.72 6.00 10.39 11.83 28.83 13.67 11.1 37.77 20.66 13.75 6.08 10.28 11.92 30.9 13.52 –1.4 –11.8 95% CI 8.95 to 25.78 2.65 to 20.61 –21.37 to 12.7 5.35 to 20.1 9.25 to 38.51 10.57 to 32.08 5.38 to 22.06 –4.54 to 16.54 1.32 to 19.47 3.24 to 20.42 15.6 to 42.07 5.99 to 21.34 0.26 to 21.94 3.24 to 72.3 10.07 to 31.24 5.34 to 22.15 –4.5 to 16.67 1.22 to 19.35 3.4 to 20.44 17.21 to 44.58 6.22 to 20.82 –39.67 to 36.88 –468.22 to 444.62 p-Value < 0.001 0.011 0.618 0.001 0.001 < 0.001 0.001 0.265 0.025 0.007 < 0.001 < 0.001 0.045 0.032 < 0.001 0.001 0.26 0.026 0.006 < 0.001 < 0.001 0.943 0.96 pintc 0.016(codominant) 0.115(dominant) 0.017(codominant) 0.006(recessive) 0.156(recessive) 0.022(codominant) 0.003(recessive) 0.434(codominant) ) ra40 e y / L20 m ( 5 7– 0 5 2 F FE–20 GG CG CC CC GG AG AA GG CG CC Genotype p53 R72P; rs1042522 p21 S31R; rs1801270 CA or AAd CCND1 P242P; rs9344 CCND1 –7006G>C; rs667515 CCND1 haplotype 1 (rs667515, rs9344)e –/– GG/– GG/GG CCND1 haplotype 2 (rs667515, rs9344)e CCND1 haplotype 3 (rs667515, rs9344)e CCND1 haplotype 4 (rs667515, rs9344)e –/– GA/– GA/GA –/– CG/– CG/CG –/– CA/– CA/CA Discussion Understanding the pathways by which PM10 damages lung structures and identify- ing susceptible subjects are important steps in managing the public health challenges of anthropogenic ambient air pollution. In this study, we present novel evidence that genetic polymorphisms in the cell fate controlling genes, p53, p21, and CCND1 may modify the degree to which adults benefit from improved air quality. If confirmed by independent stud- ies, the results are of public health relevance. The observed difference between genotype subgroups with regard to ΔPM10 effects on average lung function decline ranged between 11 mL/year and 21 mL/year for FEF25–75. This difference compares with the observed excess mean annual decline in FEF25–75 of 18 mL and 14 mL per pack per day smoked during follow-up by, respectively, male and female SAPALDIA participants who smoked at baseline (modeled according to Downs et al. 2005). This difference in lung function decline may seem small in absolute terms and from an individual perspective, but even slight shifts in the population distribution of lung function can substantially increase the prevalence of subjects exhibiting respiratory function below clinical thresholds. In addi- tion, lung function is known to be a strong and independent predictor of overall mortal- ity (Künzli et al. 2000a, 2000b). The mechanisms by which air pollutants induce harmful changes in bronchial tissue and ultimately lead to respiratory symptoms and clinically relevant respiratory dysfunc- tion have been investigated. It seems well established that PM directly increases oxida- tive stress (Donaldson et al. 2003), activates the expression of proinflammatory cyto- kines (e.g., tumor necrosis factor α, nuclear factor-κβ, and interleukin-8) (Rahman et al. 2002) and induces the homing of inflamma- tory cells such as neutrophils, alveolar macro- phages, and dendritic cells, thus resulting in inflammation of the lung (Behndig et al. 2006; Bosson et al. 2008; Li et al. 1996,1997; Nightingale et al. 2000). The toxic effects of PM are further enhanced by bronchial tissue injuries and increased epithelial permeability (Morrison et al. 1999). Our results are in line with more recent in vitro experiments with different types of bronchial cell lines demonstrating that PM induces cell proliferation arrest and apoptosis in exposed cells (Bayram et al. 2006; Dagher et al. 2006; Rosas Perez et al. 2007; Soberanes et al. 2006; Upadhyay et al. 2003; Zhang et al. 2007). Air pollutants or cigarette smoke, both exhibiting oxidative properties, specifi- cally alter the expression levels of tumor sup- pressor genes such as p53 and p21 and of the cell cycle control gene CCND1 in human and rodent in vitro bronchial cell culture