ROLE OF GABAERGIC SYSTEM GENETIC POLYMORPHISMS IN THE DEVELOPMENT OF OBSTRUCTIVE SLEEP APNEA SYNDROME IN ASTHMA PATIENTS

The results of recent studies indicate the potential role of gamma-aminobutyric acid (GABA), as an inhibitory mediator of the central nervous system, in the pathogenesis of obstructive sleep apnea syndrome (OSAS) - a common disorder that often accompanies asthma. The aim of the study was to investigate the possible role of some GABAergic system genetic polymorphisms in the formation of OSAS in asthma patients. Overnight cardiorespiratory monitoring was performed to diagnose OSAS and spirometry was conducted to evaluate the airway reactivity to the bronchodilator fenoterol in 184 asthma patients. Polymorphisms of GAD1 , GAD2 , GABBR1 and GABBR2 genes (15 polymorphisms in total) were genotyped by LATE-PCR method. Significant results were obtained for rs3749034 polymorphism of GAD1 gene and rs35400353 of GABBR2 in association analysis with the presence of OSAS. rs3749034 significantly influenced the presence of OSAS in males, which was accompanied by the predominance of the CC genotype among patients with OSAS, while CT+TT genotypes were more common in patients without OSAS (OR 3.9 95%CI [1.36-11.67], p=0.01). In total sample GAD1 rs3749034 polymorphism was an independent factor increasing the likelihood of having OSAS after adjustment for significant confounders (OR 1.9 95%CI [1.23-3.15], p=0.005). rs35400353 polymorphism was also associated with OSAS after adjustment for confounders, although its relationship was less significant (OR 1.5 95%CI [1.1-2.3], p=0.04). There was a tendency for interrelation with airway hyperresponsiveness to bronchodilator for both polymorphisms: rs3749034 - in case of CT+TT genotypes, rs35400353 - in case of DD genotype. rs3749034 polymorphism also significantly influenced lung function parameters. After additional verification of the results, the identified genetic polymorphisms may be used to individually predict the risk of OSAS as well as for the development of personalized approaches in asthma treatment using GABA.

obstructive sleep apnea syndrome, asthma, genetic polymorphism, gamma-aminobutyric acid, airway hyperresponsiveness

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23. Dicpinigaitis P.V., Nierman D.M., Miller A. Baclofen-induced bronchoconstriction. Ann. Pharmacother. 1993; 27(7-8):883-884.

24. Dicpinigaitis P.V. Effect of the GABA-agonist baclofen on bronchial responsiveness in asthmatics. Pulm. Pharmacol. Ther. 1999; 12(4):257-260.

25. Dimić D., Timotijevic L., Nikolic I., Zdravkovic A., Nikcevic L., Dimic N., Simeunovic I. Effects of GABA on lung function in asthmatics after methacholine inhalation. Eur. Respir. J. 2017; 50:PA3574. doi: 10.1183/1393003.congress-2017.PA3574

26. Finnimore A.J., Roebuck M., Sajkov D., McEvoy R.D. The effects of the GABA agonist, baclofen, on sleep and breathing. Eur. Respir. J. 1995; 8(2):230-234.

27. Kheirandish-Gozal L., McManus C.J.T., Kellermann G.H., Samiei A., Gozal D. Urinary neurotransmitters are selectively altered in children with obstructive sleep apnea and predict cognitive morbidity. Chest 2013; 143(6):1576-1583. doi: 10.1378/chest.12-2606

28. Kong D.L., Qin Z., Shen H., Jin H.Y., Wang W., Wang Z.F. Association of obstructive sleep apnea with asthma: a meta-analysis. Sci. Rep. 2017; 7(1):4088. doi: 10.1038/s41598-017-04446-6

29. Lett T.A., Kennedy J.L., Radhu N., Dominguez L.G., Chakravarty M.M., Nazeri A., Farzan F., Walter H., Heinz A., Mulsant B.H., Daskalakis Z.J., Voineskos A.N. Prefrontal white matter structure mediates the influence of GAD1 on working memory. Neuropsychopharmacology 2016; 41(9):2224-2231. doi: 10.1038/npp.2016.14

30. Li Z., Tang T., Du J., Wu W., Zhou X., Qin G. Association between single nucleotide polymorphisms in gamma-aminobutyric acid B receptor, insulin receptor substrate-1, and hypocretin neuropeptide precursor genes and susceptibility to obstructive sleep apnea hypopnea syndrome in a Chinese Han population. Med. Princ. Pract. 2016; 25(6):517-524.

31. Piovezan R.D., Kase C., Moizinho R., Tufik S., Poyares D. Gabapentin acutely increases the apnea-hypopnea index in older men: data from a randomized, double-blind, placebo-controlled study. J. Sleep Res. 2017; 26(2):166-170. doi: 10.1111/jsr.12495

32. Redline S., Tishler P.V. The genetics of sleep apnea. Sleep Med. Rev. 2000; 4(6):583-602.

33. Sanchez J.A., Pierce K.E., Rice J.E., Wangh L.J. Linear-after-the-exponential (LATE)-PCR: an advanced method of asymmetric PCR and its uses in quantitative real-time analysis. Proc. Natl. Acad. Sci. USA 2004; 101(7):1933-1938.

34. Senaratna C.V., Perret J.L., Lodge C.J., Lowe A.J., Campbell B.E., Matheson M.C., Hamilton G.S., Dharmage S.C. Prevalence of obstructive sleep apnea in the general population: A systematic review. Sleep Med. Rev. 2017; 34:70-81. doi: 10.1016/j.smrv.2016.07.002

35. Sheludko E., Naumov D., Kotova O., Perelman J., Kolosov V. Evidence of association between GABBR2 gene polymorphism and obstructive sleep apnea syndrome in asthma patients. Respirology. 2017; 22(Suppl.3):37.

36. Taillé C., Rouvel-Tallec A., Stoica M., Danel C., Dehoux M., Marin-Esteban V., Pretolani M., Aubier M., d'Ortho M.P. Obstructive sleep apnoea modulates airway inflammation and remodelling in severe asthma. PLoS One 2016; 11(3):e0150042. doi: 10.1371/journal.pone.0150042

37. Teodorescu M., Polomis D.A., Hall S.V., Teodorescu M.C., Gangnon R.E., Peterson A.G., Xie A., Sorkness C.A., Jarjour N.N. Association of obstructive sleep apnea risk with asthma control in adults. Chest 2010; 138(3):543-550. doi: 10.1378/chest.09-3066

38. Weber H., Scholz C.J., Domschke K., Baumann C., Klauke B., Jacob C.P., Maier W., Fritze J., Bandelow B., Zwanzger P.M., Lang T., Fehm L., Ströhle A., Hamm A., Gerlach A.L., Alpers G.W., Kircher T., Wittchen H.U., Arolt V., Pauli P., Deckert J., Reif A. Gender differences in associations of glutamate decarboxylase 1 gene (GAD1) variants with panic disorder. PLoS One 2012; 7(5):e37651. doi: 10.1371/journal.pone.0037651