A genome-wide SNP-by-NO2 interaction study on lung function in the LifeLines study

Background: Long-term exposure to ambient NO2 levels, representing traffic related air pollution (TRAP), has been associated with lower lung function in the general population. However, since some individuals are more prone to the deleterious effects of TRAP, genetic susceptibility might play a role. Aim: To perform a hypothesis free genome-wide interaction study to assess SNP-by-NO2 interactions in relation to lung function. Methods: 7,653 subjects from the LifeLines cohort and 227,981 SNPs were included in the analysis. SNP-by-NO2 exposure interactions and their association with FEV1 and FEV1/FVC were tested using additive genetic models adjusted for confounders. The genome-wide significant threshold was an interaction p-value (Pint) <2.19*10<−7, and SNPs with Pint <1*10<−4 were further investigated. SNP-expression associations in lung tissue and whole blood were assessed using GTEx portal. Results: We found 13 and 15 independent SNP-by-NO2 interactions in association with FEV1 and FEV1/FVC, respectively (Pint <10<−4, none were genome-wide significant). No of these SNPs were previously identified in genome wide association studies on lung function. TopSNP rs17539875 in REV3L was associated with expression of a neighboring gene KIAA1919 in lung tissue (p=4.25*10−5) and rs3742188 in RAB20 was associated with RAB20-expression in whole blood (p=4.84*10−5). Conclusions: We identified candidate genes that might underlie susceptibility to TRAP exposure in relation to lower lung function levels. However, future studies including the complex mixture of all air pollutants should be conducted to validate these findings followed by functional studies to explain why these genes alter the susceptibility to TRAP.