Association between Polymorphisms in Bitter Taste Receptor Genes and Clinical Features in Korean Asthmatics

Background: Bitter taste receptors (TAS2R) in human airway smooth muscle have recently been shown to have an important role in bronchodilation, together with β2-adrenergic receptors. Object: To evaluate the association between genetic variations in TAS2R and clinical features, including bronchodilator response and asthma control. Method: We analyzed the association between single nucleotide polymorphisms (SNPs) of TAS2R10 and TAS2R14 and variables such as demographic data, atopy, duration of disease, and asthma control status, including variables such as asthma control test (ACT) score, percent predicted value of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio, as well as bronchodilator response (BDR), in 721 asthma patients in Korea. Result: Three novel SNPs of 633G>A, 645C>A, and -79G>A in TAS2R10 and 3 known SNPs of -815T>C, -1267G>A, and -1897T>C in TAS2R14 were analyzed. Increased BDR was significantly associated with SNPs of -815T>C [OR (95% CI) = 1.88 (1.01-3.49), p = 0.04 ] [J Gen Physiol 2005;125:535-553; Am J Respir Cell Mol Biol 2010;42:373-3812], -1267A>G [OR (95% CI) = 2.07 (1.03-4.15), p = 0.04] and -1897T>C [OR (95% CI) = 3.05 (1.01-9.23), p = 0.04, in a dominant model, and OR = 1.91 (1.08−3.36), p = 0.02, in a codominant model] of the TAS2R14 gene. There was a significant association between -815T>C and a low mean ACT score [OR (95% CI) = 5.84 (1.94-17.61), p = 0.001]. In haplotype analysis, TAC, CAT, and TGT, or TG and CA haplotypes on TAS2R14 were significantly associated with increased BDR; CAT and CA haplotypes were significantly associated with a low ACT score. Conclusion: Genetic variations in TAS2Rs may be valuable genetic markers to predict therapeutic response and outcomes in asthma. Further research in an independent cohort is needed.

[1]  J. Stockman.  Effect of Bronchoconstriction on Airway Remodeling in Asthma. , 2018, The New England journal of medicine.

[2]  M. Sanderson,et al.  Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity , 2014, British journal of pharmacology.

[3]  P. Devillier,et al.  The expression and relaxant effect of bitter taste receptors in human bronchi , 2013, Respiratory Research.

[4]  Lawrence M. Lifshitz,et al.  The Cellular and Molecular Basis of Bitter Tastant-Induced Bronchodilation , 2013, PLoS biology.

[5]  S. Dahlén,et al.  The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea. , 2012, American journal of physiology. Lung cellular and molecular physiology.

[6]  Choon-Sik Park,et al.  Identification of asthma clusters in two independent Korean adult asthma cohorts , 2012, European Respiratory Journal.

[7]  H. Logan,et al.  Variation in the gene TAS2R13 is associated with differences in alcohol consumption in patients with head and neck cancer. , 2012, Chemical senses.

[8]  Yusuke Nakamura,et al.  Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene , 2012, PLoS genetics.

[9]  Lawrence M. Lifshitz,et al.  Activation of BK channels may not be required for bitter tastant–induced bronchodilation , 2012, Nature Medicine.

[10]  S. Kinnamon,et al.  Taste receptor signalling – from tongues to lungs , 2012, Acta physiologica.

[11]  D. Hui,et al.  Evaluation of the asthma control test: A reliable determinant of disease stability and a predictor of future exacerbations , 2012, Respirology.

[12]  P. Barnes.  Severe asthma: advances in current management and future therapy. , 2012, The Journal of allergy and clinical immunology.

[13]  S. Korn,et al.  Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria. , 2011, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[14]  S. Liggett,et al.  Bronchodilator activity of bitter tastants in human tissue , 2011, Nature Medicine.

[15]  B. Levy,et al.  Faculty Opinions recommendation of Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. , 2011 .

[16]  M. Sanderson,et al.  Effects of formoterol on contraction and Ca2+ signaling of mouse airway smooth muscle cells. , 2010, American journal of respiratory cell and molecular biology.

[17]  K. Hemminki,et al.  A gene-wide investigation on polymorphisms in the taste receptor 2R14 (TAS2R14) and susceptibility to colorectal cancer , 2010, BMC Medical Genetics.

[18]  Y. Cho,et al.  Factors associated with severity and exacerbation of asthma: a baseline analysis of the cohort for reality and evolution of adult asthma in Korea (COREA). , 2009, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[19]  Yehuda Ben-Shahar,et al.  Motile Cilia of Human Airway Epithelia Are Chemosensory , 2009, Science.

[20]  E. Hillyer,et al.  The Asthma Control Test (ACT) as a predictor of GINA guideline-defined asthma control: analysis of a multinational cross-sectional survey. , 2009, Primary care respiratory journal : journal of the General Practice Airways Group.

[21]  S. Sarna,et al.  FEV1 response to bronchodilation in an adult urban population. , 2008, Chest.

[22]  Ming D. Li,et al.  Bitter taste receptor gene polymorphisms are an important factor in the development of nicotine dependence in African Americans , 2008, Journal of Medical Genetics.

[23]  S. Liggett,et al.  Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors , 2008, Proceedings of the National Academy of Sciences.

[24]  P. J. Barnes,et al.  Global strategy for asthma management and prevention: GINA executive summary , 2008, European Respiratory Journal.

[25]  T. Gudermann,et al.  Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca2+‐activated K+ channel , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  D. Curran‐Everett,et al.  Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program. , 2007, The Journal of allergy and clinical immunology.

[27]  C. Sternini.  Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[28]  D. Deshpande,et al.  Targeting G protein-coupled receptor signaling in asthma. , 2006, Cellular signalling.

[29]  Alan Kaplan,et al.  Review of 'Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths.' Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Ann Intern Med 2006;144:904-12. , 2006, Primary care respiratory journal : journal of the General Practice Airways Group.

[30]  E. Salpeter,et al.  Meta-Analysis: Effect of Long-Acting -Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths , 2006, Annals of Internal Medicine.

[31]  M. Kosinski,et al.  Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists. , 2006, The Journal of allergy and clinical immunology.

[32]  K. Kamiya,et al.  Involvement of reduced sensitivity to Ca2+ in β‐adrenergic action on airway smooth muscle , 2006 .

[33]  H. Aizawa,et al.  Determinants of Bronchodilator Responsiveness in Patients with Controlled Asthma , 2006, The Journal of asthma : official journal of the Association for the Care of Asthma.

[34]  K. Kamiya,et al.  Involvement of reduced sensitivity to Ca in beta-adrenergic action on airway smooth muscle. , 2006, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[35]  L. Bierut,et al.  Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence. , 2006, American journal of human genetics.

[36]  J. Hankinson,et al.  Interpretative strategies for lung function tests , 2005, European Respiratory Journal.

[37]  Michael J. Sanderson,et al.  The Frequency of Calcium Oscillations Induced by 5-HT, ACH, and KCl Determine the Contraction of Smooth Muscle Cells of Intrapulmonary Bronchioles , 2005, The Journal of general physiology.

[38]  E. Israel,et al.  Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial , 2004, The Lancet.

[39]  P. Sham,et al.  The future of association studies: gene-based analysis and replication. , 2004, American journal of human genetics.

[40]  J. Donohue.  Therapeutic responses in asthma and COPD. Bronchodilators. , 2004, Chest.

[41]  D. Sin,et al.  Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. , 2004, JAMA.

[42]  P. Barnes.  New drugs for asthma , 2004, Nature Reviews Drug Discovery.

[43]  T. Finger,et al.  Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. H. Young,et al.  Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  R. Hancox,et al.  The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. , 2001, American journal of respiratory and critical care medicine.

[46]  S. Sullivan,et al.  The health economics of asthma and rhinitis. I. Assessing the economic impact. , 2001, The Journal of allergy and clinical immunology.

[47]  E. Silverman,et al.  The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. , 2000, American journal of respiratory and critical care medicine.

[48]  A. Long,et al.  The power of association studies to detect the contribution of candidate genetic loci to variation in complex traits. , 1999, Genome research.

[49]  D. Drenckhahn,et al.  Identification of the taste cell G-protein, α-gustducin, in brush cells of the rat pancreatic duct system , 1998, Histochemistry and Cell Biology.

[50]  R. Hancox,et al.  Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma. , 1998, The European respiratory journal.

[51]  Brian Lipworth,et al.  Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics , 1997, The Lancet.

[52]  D. Drenckhahn,et al.  Taste receptor-like cells in the rat gut identified by expression of alpha-gustducin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[53]  I. Hall,et al.  Association of Glu 27 β2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects , 1995, The Lancet.

[54]  M. Munakata,et al.  Beta 2 adrenergic receptor gene restriction fragment length polymorphism and bronchial asthma. , 1995, Thorax.