POLYMORPHISM OF TRPM8 GENE AS AN INDEPENDENT FACTOR OF BRONCHIAL OBSUCTION IN ASTHMA

Along with chronic obstructive pulmonary disease, asthma may also be accompanied by an irreversible decrease in lung function. It is known that among other causes of this phenomenon genetic predisposition may play a certain role. The aim of the study was to investigate the effect of rs11562975 polymorphism of TRPM8 gene on lung function in patients with asthma. The study enrolled 285 patients with uncontrolled persistent mild and moderate asthma. All patients underwent standard spirometry before and 15 minutes after inhalation of fenoterol bronchodilator. rs11562975 polymorphism was genotyped using LATE-PCR. It has been established that polymorphism is significantly interrelated with a number of lung function parameters, including FEV₁/FVC. Carriage of GC and CC genotypes was accompanied by reduced values of both pre- and postbronchodilator ratio FEV₁/FVC. At the same time, the frequency of GС+СC genotypes was significantly higher among patients with baseline FEV₁/FVC<70%, and among patients with postbronchodilator FEV₁/FVC<80%. All associations of the polymorphism with FEV₁/FVC were significant regardless of gender, age, body mass index, duration of the disease, age of asthma onset, pack-year index and cold airway hyperresponsiveness. The obtained results indicate the potential presence of TRPM8-dependent component of asthma pathogenesis

TRPM8, asthma, cold receptors, TRPM8, genetic polymorphism, lung function, bronchial obstruction

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22. Bai T.R., Vonk J.M., Postma D.S., Boezen H.M. Severe exacerbations predict excess lung function decline in asthma. Eur. Respir. J. 2007; 30(3):452-456.

23. Barton S.J., Koppelman G.H., Vonk J.M., Browning C.A., Nolte I.M., Stewart C.E., Bainbridge S., Mutch S., Rose-Zerilli M.J., Postma D.S., Maniatis N., Henry A.P., Hall I.P., Holgate S.T., Tighe P., Holloway J.W., Sayers I. PLAUR polymorphisms are associated with asthma, PLAUR levels, and lung function decline. J. Allergy Clin. Immunol. 2009; 123(6):1391-1400.

24. de Marco R., Marcon A., Jarvis D., Accordini S., Bugiani M., Cazzoletti L., Cerveri I., Corsico A., Gislason D., Gulsvik A., Jõgi R., Martínez-Moratalla J., Pin I., Janson C.; ECRHS Therapy Group. Inhaled steroids are associated with reduced lung function decline in subjects with asthma with elevated total IgE. J. Allergy Clin. Immunol. 2007; 119(3):611-617.

25. Dijkstra A., Howard T.D., Vonk J.M., Ampleford E.J., Lange L.A., Bleecker E.R., Meyers D.A., Postma D.S.Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma. J. Allergy Clin. Immunol. 2006; 117(3):604-611.

26. Dijkstra A., Vonk J.M., Jongepier H., Koppelman G.H., Schouten J.P., ten Hacken N.H., Timens W., Postma D.S. Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex. Thorax 2006; 61(2): 105-110.

27. Fernández J.A., Skryma R., Bidaux G., Magleby K.L., Scholfield C.N., McGeown J.G., Prevarskaya N., Zholos A.V. Short isoforms of the cold receptor TRPM8 inhibit channel gating by mimicking heat action rather than chemical inhibitors. J. Biol. Chem. 2012; 287(5):2963-2970.

28. Fujita T., Liu Y., Higashitsuji H., Itoh K., Shibasaki K., Fujita J., Nishiyama H. Involvement of TRPV3 and TRPM8 ion channel proteins in induction of mammalian cold-inducible proteins. Biochem. Biophys. Res. Commun. 2018; 495(1):935-940.

29. Guerra S., Sherrill D.L., Kurzius-Spencer M., Venker C., Halonen M., Quan S.F., Martinez F.D. The course of persistent airflow limitation in subjects with and without asthma. Respir. Med. 2008; 102(10):1473-1482.

30. Imboden M., Bouzigon E., Curjuric I., Ramasamy A., Kumar A., Hancock D.B., Wilk J.B., Vonk J.M., Thun G.A., Siroux V., Nadif R.,and other authors Genome-wide association study of lung function decline in adults with and without asthma. J. Allergy Clin. Immunol. 2012; 129(5):1218-1228.

31. Jongepier H., Boezen H.M., Dijkstra A., Howard T.D., Vonk J.M., Koppelman G.H., Zheng S.L., Meyers D.A., Bleecker E.R., Postma D.S. Polymorphisms of the ADAM33 gene are associated with accelerated lung function decline in asthma. Clin. Exp. Allergy 2004; 34(5):757-760.

32. Lange P., Parner J., Vestbo J., Schnohr P., Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N. Engl. J. Med. 1998; 339(17):1194-1200.

33. Lee J.H., Haselkorn T., Borish L., Rasouliyan L., Chipps B.E., Wenzel S.E. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest 2007; 132(6):1882-1889.

34. Li X., Hawkins G.A., Ampleford E.J., Moore W.C., Li H., Hastie A.T., Howard T.D., Boushey H.A., Busse W.W., Calhoun W.J., Castro M., Erzurum S.C., Israel E., Lemanske R.F. Jr., Szefler S.J., Wasserman S.I., Wenzel S.E., Peters S.P., Meyers D.A., Bleecker E.R. Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients. J. Allergy Clin. Immunol. 2013; 132(2):313-320.

35. Liu H., Liu Q., Hua L., Pan J. Inhibition of transient receptor potential melastatin 8 alleviates airway inflammation and remodeling in a murine model of asthma with cold air stimulus. Acta Biochim. Biophys. Sin. (Shanghai) 2018; 50(5):499-506.

36. Loren M.L., Leung P.K., Cooley R.L., Chai H., Bell T.D., Buck V.M. Irreversibility of obstructive changes in severe asthma in childhood. Chest 1978; 74(2):126-129.

37. Panizza J.A., James A.L., Ryan G., de Klerk N., Finucane K.E. Mortality and airflow obstruction in asthma: a 17-year follow-up study. Intern. Med. J. 2006: 36(12):773-780.

38. ten Brinke A. Risk factors associated with irreversible airflow limitation in asthma. Curr. Opin. Allergy Clin. Immunol. 2008; 8(1):63-69.

39. ten Brinke A., Zwinderman A.H., Sterk P.J., Rabe K.F., Bel E.H. Factors associated with persistent airflow limitation in severe asthma. Am. J. Respir. Crit. Care Med. 2001; 164(5):744-748.

40. Vonk J.M., Jongepier H., Panhuysen C.I., Schouten J.P., Bleecker E.R., Postma D.S. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax 2003; 58(4):322-327.