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  • Impact of TAS2R38 polymorphisms on nasal nitric oxide and Pseudomonas infections in primary ciliary dyskinesia: relation to genotype

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Respiratory infection
Original research
Impact of TAS2R38 polymorphisms on nasal nitric oxide and Pseudomonas infections in primary ciliary dyskinesia: relation to genotype
  1. Massimo Pifferi1,
  2. Attilio Boner2,
  3. Debora Maj1,
  4. Angela Michelucci3,
  5. Gabriele Donzelli4,
  6. Angela M Cangiotti5,
  7. Raffaella Guazzo6,
  8. Giulia Bertolucci1,
  9. Veronica Bertini7,
  10. Chiara Doccioli8,
  11. Michele Piazza2,
  12. Angelo Valetto7,
  13. Maria Adelaide Caligo3,
  14. Diego Peroni1,
  15. Andrew Bush9,10
  1. 1Department of Pediatrics, Pisa University Hospital, Pisa, Italy
  2. 2Department of Surgical Science, Dentistry, Gynecology and Pediatrics, Integrated University Hospital of Verona, Verona, Italy
  3. 3Laboratory of Molecular Genetics, Pisa University Hospital, Pisa, Italy
  4. 4Institute of Clinical Physiology National Research Council, Pisa, Italy
  5. 5Institute of Normal Human Morphology, Electron Microscopy Unit, University Hospital of Ancona Umberto I G M Lancisi G Salesi, Ancona, Italy
  6. 6Laboratory of Electron Microscopy, Pathology Unit, Siena University Hospital, Siena, Italy
  7. 7Laboratory of Cytogenetics, Pisa University Hospital, Pisa, Italy
  8. 8Department of Statistics, Computer Science and Applications, University of Florence, Florence, Italy
  9. 9Imperial College London, London, UK
  10. 10Royal Brompton Hospital, London, UK
  1. Correspondence to Dr Massimo Pifferi, Department of Pediatrics, Pisa University Hospital, Via Roma 67 - 56126 Pisa, Italy; m.pifferi{at}med.unipi.it

Abstract

Objective Primary ciliary dyskinesia (PCD) severity has been related to genotype and levels of nasal nitric oxide (nNO). The most common TAS2R38 haplotypes (PAV/PAV, PAV/AVI, AVI/AVI) encoding the bitter taste receptor can affect nNO levels and thus could play a role in the susceptibility to respiratory infections. We assessed the impact of these polymorphisms on nNO production and Pseudomonas aeruginosa (P.a.) infections in different PCD genotypes.

Methods Prospective, longitudinal, single-centre study in patients with PCD with known genotype and one of three TAS2R38 haplotypes evaluated for up to 10 years. We related nNO values to TAS2R38 haplotypes in all patients, and in the three most frequent genotypes (CCDC39/CCDC40, DNAH5, DNAH11). In the genetic group(s) with different mean trends of nNO in relation to the polymorphism, we evaluated longitudinal lung function as a clinical outcome measure. We also studied any associations between the prevalence of chronic P.a. infection and PAV alleles. Linear mixed-effects models were used to evaluate longitudinal associations.

Results 119 patients with PCD underwent 1116 study visits. Only in the DNAH11 mutations group was there a mean trend of nNO production which was significantly higher in PAV/PAV than AVI/AVI haplotype (p=0.033), with a better trend in spirometric and plethysmographic parameters. In patients with DNAH11 mutations the PAV allele was also associated with a significantly reduced prevalence of chronic P.a. infection.

Conclusion TAS2R38 may be a modifier gene for PCD severity, but only in mild phenotype disease. Further study of TAS2R38 polymorphisms might enable new management strategies to prevent chronic P.a. infections.

  • Primary ciliary dyskinesia
  • Rare lung diseases
  • Bacterial Infection

Data availability statement

Data are available upon reasonable request. De-identified participant data are available from the corresponding author upon reasonable request, subject to the terms of Ethics Committee approval.

https://doi.org/10.1136/thorax-2024-221396

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    Data availability statement

    Data are available upon reasonable request. De-identified participant data are available from the corresponding author upon reasonable request, subject to the terms of Ethics Committee approval.

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    Footnotes

    • Contributors MPif, ABo, DM and ABu designed the study, analysed all data, wrote the manuscript. MPif, DM, AM, AMC, RG, GB, MPia and VB collected the experimental data, and contributed to data evaluation. GD and CD participated in processing data and performed the statistical analysis. MAC, AV and DP contributed to interpretation of data, and helped to draft the manuscript for important intellectual content. All authors revised the report and approved the final version before submission. MPif is the guarantor of the article and all authors take responsibility for the content of the manuscript, the integrity of the data and the accuracy of the data analysis.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.