DNA Repair Gene XPC Modifies the Association Between Air Pollution and Childhood Bronchitis

Abstract

Gene-environment interactions have been investigated for chronic diseases such as asthma, cancer etc. but acute disease like bronchitis has rarely been studied. We investigated interaction between ambient PM2.5 and single nucleotide polymorphisms (SNP) in XPC gene (rs2228001 and rs2733532) with bronchitis in 0-2 year old children. A stratified random sample of 1133 Czech children born between 1994 and 1998 in two districts, were prospectively followed daily since birth, of which 626 were genotyped. Pediatrician-diagnosed bronchitis episodes were obtained from the medical records. Central-site monitors measured air pollution exposure, which were validated. We used logistic regression and estimated coefficients using generalized estimating equations. Interaction was assessed between PM2.5 and genes and (PM) associations were presented for each genotype. Departure from additivity and multiplicativity were assessed. False discovery rate was used to adjust for multiple comparisons. There were 803 bronchitis episodes with an incidence of 56/1000 child-months. PM2.5 interactions with two XPC SNPs (rs2228001 and rs2733532) remained significant after accounting for multiple comparisons and those with CC alleles for these SNPs had more than doubling of odds, OR=2.65 (95% CI: 1.91, 3.69) and 2.72 (95% CI: 1.95, 3.78), respectively, per 25μg/m3 increase in exposure. Children with joint exposures (CC alleles and PM2.5) had significantly higher association than the additive (1.5 times) or multiplicative (2.5 times) combination of either association (Table1). A comparison of characteristics of children in the parent study with those in this study shows no selection bias. Ethnic heterogeneity did not explain the results. This is the first study to show DNA repair gene XPC may play a key role in pollution-induced pathogenesis of acute inflammatory bronchitis. XPC initiated nuclear excision repair may be relevant for PM2.5 induced oxidative DNA damage in the bronchial epithelium.