Association of TAS2R3, TAS2R4 and TAS2R5 gene polymorphism with predisposition to asthma

Introduction. It is known that bitter taste receptors (TAS2R) are expressed on many cells of the respiratory system and their activation is accompanied by a wide range of potentially beneficial effects for the treatment of asthma.

Aim. To evaluate the influence of TAS2R3, TAS2R4 and TAS2R5 polymorphisms on the development of asthma, parameters of lung function and control of the disease.

Materials and methods. The study enrolled 240 patients with asthma of varying severity (mean age 43.9±1.03 years, 44.5% males) and 90 healthy volunteers (control group, mean age 38.0±1.09 years, 50% males). Lung function was assessed using standard spirometry, the disease control was determined by ACT questionnaire. Preliminary screening by minor allele frequency, prediction of functional significance and assessment of linkage disequilibrium allowed us to select TAS2R4 rs33920115 as a representative variant for the group of TAS2R3, TAS2R4 and TAS2R5 polymorphisms. Genotyping was performed by PCR with high-resolution melting analysis.

Results. rs33920115 polymorphism was significantly associated with asthma in codominant (p=0.01), dominant (p=0.006), recessive (p=0.03), log-additive (p=0.003) and multiplicative (p=0.003) genetic models. Carriage of the AA genotype was more often observed among patients with asthma (29.2% vs. 17.8%) while the GG homozygotes were prevalent in the control group (33.3% vs. 19.2%). The effect remained significant after adjustment for sex and age (OR 1.8; 95%CI (1.26-2.61), p=0.001 for log-additive model). We found no effect of rs33920115 on lung function and asthma control.

Conclusion. TAS2R4 rs33920115 polymorphism and associated variations in TAS2R3 and TAS2R5 genes may influence the predisposition to asthma development, probably due to changes in the expression of the corresponding receptors.

1. Song P., Adeloye D., Salim H., Dos Santos J.P., Campbell H., Sheikh A., Rudan I. Global, regional, and national prevalence of asthma in 2019: a systematic analysis and modelling study. J. Glob. Health. 2022; 29(12):04052. https://doi.org/10.7189/jogh.12.04052

2. Liu H., Zhang J., Liu L., Lian G., Shi R., Xu M., Yang J., Liu X. Global disease burden and attributable risk factor analysis of asthma in 204 countries and territories from 1990 to 2019. Allergy Asthma Immunol. Res. 2023; 15(4):473– 495. https://doi.org/10.4168/aair.2023.15.4.473

3. Davitte J., DeBarmore B., Hinds D., Zhang S., Chao J., Sansbury L. Asthma control among treated US asthma patients in Practice Fusion's electronic medical record research database. NPJ Prim. Care Respir. Med. 2023; 33(1):17. https://doi.org/10.1038/s41533-023-00338-7

4. Narasimhan K. Difficult to treat and severe asthma: management strategies. Am. Fam. Physician. 2021; 103(5):286– 290.

5. Cevhertas L., Ogulur I., Maurer D.J., Burla D., Ding M., Jansen K., Koch J., Liu C., Ma S., Mitamura Y., Peng Y., Radzikowska U., Rinaldi A.O., Satitsuksanoa P., Globinska A., van de Veen W., Sokolowska M., Baerenfaller K., Gao Y.D., Agache I., Akdis M., Akdis C.A. Advances and recent developments in asthma in 2020. Allergy 2020; 75(12):3124– 3146. https://doi.org/10.1111/all.14607

6. Grassin-Delyle S., Abrial C., Fayad-Kobeissi S., Brollo M., Faisy C., Alvarez J.C., Naline E., Devillier P. The expression and relaxant effect of bitter taste receptors in human bronchi. Respir. Res. 2013; 14(1):134. https://doi.org/10.1186/1465–9921–14–134

7. Sharma P., Yi R., Nayak A.P., Wang N., Tang F., Knight M.J., Pan S., Oliver B., Deshpande D.A. Bitter taste receptor agonists mitigate features of allergic asthma in mice. Sci. Rep. 2017; 7:46166. https://doi.org/10.1038/srep46166

8. Yoon S.Y., Shin E.S., Park S.Y., Kim S., Kwon H.S., Cho Y.S., Moon H.B., Kim T.B. Association between polymorphisms in bitter taste receptor genes and clinical features in Korean asthmatics. Respiration 2016; 91(2):141–150. https://doi.org/10.1159/000443796

9. Kim D., An S.S., Lam H., Leahy J.W., Liggett S.B. Identification and characterization of novel bronchodilator agonists acting at human airway smooth muscle cell TAS2R5. ACS Pharmacol. Transl. Sci. 2020; 3(6):1069–1075. https://doi.org/10.1021/acsptsci.0c00127

10. Orsmark-Pietras C., James A., Konradsen J.R., Nordlund B., Söderhäll C., Pulkkinen V., Pedroletti C., Daham K., Kupczyk M., Dahlén B., Kere J., Dahlén S.E., Hedlin G., Melén E. Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics. Eur. Respir. J. 2013; 42(1):65–78. https://doi.org/10.1183/09031936.00077712

11. Boyle A.P., Hong E.L., Hariharan M, Cheng Y., Schaub M.A., Kasowski M., Karczewski K.J., Park J., Hitz B.C., Weng S., Cherry J.M., Snyder M. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012; 22(9):1790–1797. https://doi.org/10.1101/gr.137323.112

12. McLaren W., Gil L., Hunt S.E., Riat H.S., Ritchie G.R., Thormann A., Flicek P., Cunningham F. The Ensembl variant effect predictor. Genome Biol. 2016; 17(1):122. https://doi.org/10.1186/s13059-016–0974–4

13. Xu Z., Taylor J.A. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res. 2009; 37:W600–5. https://doi.org/10.1093/nar/gkp290

14. Machiela M.J., Chanock S.J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015; 31(21):3555–3557. https://doi.org/10.1093/bioinformatics/btv402

15. Kook J.H., Kim H.K., Kim H.J., Kim K.W., Kim T.H., Kang K.R., Oh D.J., Lee S.H. Increased expression of bitter taste receptors in human allergic nasal mucosa and their contribution to the shrinkage of human nasal mucosa. Clin. Exp. Allergy 2016; 46(4):584–601. https//doi.org/10.1111/cea.12727

16. Tokmakova A., Kim D., Guthrie B., Kim S.K., Goddard W.A. 3rd, Liggett S.B. Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes. iScience 2023; 26(4):106422. https://doi.org/10.1016/j.isci.2023.106422