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Background: Current knowledge suggests that the gene region containing MUC5B and TOLLIP plays a role in airway defence and airway inflammation, and hence respiratory disease. It is also known that exposure to air pollution increases susceptibility to respiratory disease. We aimed to study whether the effect of air pollutants on the immune response and respiratory symptoms in infants may be modified by polymorphisms in MUC5B and TOLLIP genes., Methods: 359 healthy term infants from the prospective Basel-Bern Infant Lung Development (BILD) birth cohort were included in the study. The main outcome was the score of weekly assessed respiratory symptoms in the first year of life. Using the candidate gene approach, we selected 10 single nucleotide polymorphisms (SNPs) from the MUC5B and TOLLIP regions. Nitrogen dioxide (NO 2 ) and particulate matter ≤10 μm in aerodynamic diameter (PM 10 ) exposure was estimated on a weekly basis. We used generalised additive mixed models adjusted for known covariates. To validate our results in vitro, cells from a lung epithelial cell line were downregulated in TOLLIP expression and exposed to diesel particulate matter (DPM) and polyinosinic-polycytidylic acid., Results: Significant interaction was observed between modelled air pollution (weekly NO 2 exposure) and 5 SNPs within MUC5B and TOLLIP genes regarding respiratory symptoms as outcome: E.g., infants carrying minor alleles of rs5744034, rs3793965 and rs3750920 (all TOLLIP) had an increased risk of respiratory symptoms with increasing NO 2 exposure. In vitro experiments showed that cells downregulated for TOLLIP react differently to environmental pollutant exposure with DPM and viral stimulation., Conclusion: Our findings suggest that the effect of air pollution on respiratory symptoms in infancy may be influenced by the genotype of specific SNPs from the MUC5B and TOLLIP regions. For validation of the findings, we provided in vitro evidence for the interaction of TOLLIP with air pollution., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Urs Frey reports financial support was provided by Swiss National Science Foundation. Celine Ruettimann reports a relationship with Freie Akademische Gesellschaft Basel that includes: funding grants. Philipp Latzin reports a relationship with Vertex that includes: board membership, funding grants, and speaking and lecture fees. Philipp Latzin reports a relationship with Vifor Pharma Switzerland SA that includes: speaking and lecture fees. Philipp Latzin reports a relationship with OM Pharma Ltd that includes: board membership, funding grants, and speaking and lecture fees. Philipp Latzin reports a relationship with Polyphor Ltd that includes: board membership. Philipp Latzin reports a relationship with Santhera Pharmaceuticals Schweiz AG that includes: board membership. Philipp Latzin reports a relationship with Allecra Therapeutics that includes: board membership. Philipp Latzin reports a relationship with Sanofi that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)