TOLLIP and MUC5B modulate the effect of ambient NO2 on respiratory symptoms in infancy

Olga Gorlanova; Céline Rüttimann; Andras Soti; Kees de Hoogh; Danielle Vienneau; Noëmi Künstle; Carla Rebeca Da Silva Sena; Ruth Steinberg; Xenia Bovermann; Sven Schulzke; Philipp Latzin; Martin Röösli; Urs Frey; Loretta Müller

doi:10.1016/j.chemosphere.2024.142837

TOLLIP and MUC5B modulate the effect of ambient NO₂ on respiratory symptoms in infancy

Chemosphere. 2024 Sep:363:142837. doi: 10.1016/j.chemosphere.2024.142837. Epub 2024 Jul 14.

Affiliations

¹ University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland; Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
² Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Paediatrics and Youth Medicine, Clinic Donaustadt, Vienna, Austria.
³ Swiss Tropical and Public Health Institute Basel, Allschwil, Switzerland; University of Basel, Basel, Switzerland.
⁴ University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland; Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Priority Research Centre GrowUpWell® and Hunter Medical Research Institute, University of Newcastle, NSW, Australia.
⁵ University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.
⁶ Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁷ University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. Electronic address: urs.frey@ukbb.ch.
⁸ Division of Paediatric Respiratory Medicine and Allergology, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Lung Precision Medicine, Department for BioMedical Research (DBMR), University of Bern, Switzerland.

PMID: 39009092
DOI: 10.1016/j.chemosphere.2024.142837

Abstract

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 (NO₂) and particulate matter ≤10 μm in aerodynamic diameter (PM₁₀) 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 NO₂ 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 NO₂ 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.

Keywords: Air pollution; Gene–environment interaction; Infancy; MUC5B; Respiratory symptoms; TOLLIP.

MeSH terms

Air Pollutants* / toxicity
Air Pollution / adverse effects
Environmental Exposure / adverse effects
Female
Humans
Infant
Infant, Newborn
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Male
Mucin-5B* / genetics
Nitrogen Dioxide* / toxicity
Particulate Matter / toxicity
Polymorphism, Single Nucleotide*
Prospective Studies
Respiratory Tract Diseases / chemically induced
Respiratory Tract Diseases / genetics

Substances

Mucin-5B
Air Pollutants
MUC5B protein, human
Nitrogen Dioxide
TOLLIP protein, human
Intracellular Signaling Peptides and Proteins
Particulate Matter