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Published on: August 7, 2017
TOLLIP and MUC5B modulate the effect of ambient NO2 on respiratory symptoms in infancy
Olga Gorlanova1, Céline Rüttimann1, Andras Soti2
1University 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.
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.
Insights
Infant respiratory symptoms are linked to air pollution exposure, with genetic variations in MUC5B and TOLLIP genes influencing this risk. These findings highlight the role of specific gene polymorphisms in modulating responses to environmental pollutants.
Area of Science:
- Environmental Health
- Genetics
- Immunology
Background:
- The MUC5B and TOLLIP gene region is implicated in airway defense and inflammation, relevant to respiratory diseases.
- Air pollution exposure is a known risk factor for increased susceptibility to respiratory illnesses.
Purpose of the Study:
- To investigate if genetic variations in MUC5B and TOLLIP modify the impact of air pollutants on infant immune response and respiratory symptoms.
- To explore the interaction between air pollution exposure and specific gene polymorphisms in infants.
Main Methods:
- A prospective birth cohort study (BILD) included 359 healthy term infants.
- Weekly respiratory symptom scores were the primary outcome, with weekly air pollutant (NO2, PM10) exposure estimation.
- Candidate gene approach identified 10 single nucleotide polymorphisms (SNPs) in MUC5B and TOLLIP.
- Generalized additive mixed models were used for analysis, with in vitro validation using lung epithelial cells.
Main Results:
- Significant interactions were found between weekly nitrogen dioxide (NO2) exposure and 5 SNPs in MUC5B and TOLLIP genes concerning respiratory symptoms.
- Infants with minor alleles in specific TOLLIP SNPs (rs5744034, rs3793965, rs3750920) showed increased respiratory symptom risk with higher NO2 exposure.
- In vitro studies demonstrated altered cellular responses to diesel particulate matter and viral stimulation in TOLLIP-downregulated cells.
Conclusions:
- Infant respiratory symptoms related to air pollution may be influenced by genetic variations in MUC5B and TOLLIP SNPs.
- In vitro evidence supports the interaction between TOLLIP and air pollution, validating the study's findings.
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