Abstract
BackgroundOxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes.ObjectivesWe studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures.MethodsFor 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV1), FEV1 over forced vital capacity (FEV1/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF25-75) was regressed on interval exposure to particulate matter <10 µm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (pinteraction<0.05). Replication was attempted for SNPs with MAF>10% in 3320 SAPALDIA participants without GWAS.ResultsOn the SNP-level, rs2035268 in gene SNCA accelerated FEV1/FVC decline by 3.8% (pinteraction = 2.5×10−6), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml pinteraction = 9.7×10−8) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (pinteraction = 3.0×10−4) on FEV1/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful.ConclusionsConsistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobacco smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challenging.
Highlights
Lung function is an important determinant of respiratory health and life expectancy [1,2,3,4]
In the present study we studied the decline of FEV1, the ratio FEV1/forced vital capacity (FVC) and FEF25–75 between 1991 and 2002, as measures of airway obstruction, calculated by subtracting the first measurement from the second
Characteristics of Study Population Regarding the distribution of sex, age and lung function according to categories of smoking and PM10 exposure, our study sample on average presented decreasing lung function values and accelerated lung function decline with increased smoking (Table 2)
Summary
Lung function is an important determinant of respiratory health and life expectancy [1,2,3,4]. Polymorphisms in oxidative stress related candidate genes like gluthathione s-transferases (GSTs), microsomal epoxide hydroxylase (EPHX), or heme-oxygenase 1 (HMOX-1), have been associated with lung function decline and chronic obstructive pulmonary disease (COPD), a disease characterized by accelerated, progressive lung function loss [13,14,15,16]. Most of these candidate genes have not been consistently replicated across studies and populations according to a recent review [15]. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes
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