cfpdБюллетень физиологии и патологии дыханияBulletin Physiology and Pathology of Respiration1998-5029Дальневосточный научный центр физиологии и патологии дыхания10.12737/article_5c898885553e15.87371124cfpd-187Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHРОЛЬ ПОЛИМОРФИЗМОВ ГЕНОВ ГАМКЕРГИЧЕСКОЙ СИСТЕМЫ В ФОРМИРОВАНИИ СИНДРОМА ОБСТРУКТИВНОГО АПНОЭ СНА У БОЛЬНЫХ БРОНХАЛЬНОЙ АСТМОЙROLE OF GABAERGIC SYSTEM GENETIC POLYMORPHISMS IN THE DEVELOPMENT OF OBSTRUCTIVE SLEEP APNEA SYNDROME IN ASTHMA PATIENTSШелудькоЕ. Г.SheludkoE. G.noemail@neicon.ruНаумовД. Е.NaumovD. E.noemail@neicon.ruГассанД. А.GassanD. A.noemail@neicon.ruКотоваО. О.KotovaO. O.noemail@neicon.ruКолосовВ. П.KolosovV. P.noemail@neicon.ruФедеральное государственное бюджетное научное учреждение «Дальневосточный научный центр физиологии и патологии дыхания»Far Eastern Scientific Center of Physiology and Pathology of Respiration2019181120190713744Copyright © Шелудько Е.Г., Наумов Д.Е., Гассан Д.А., Котова О.О., Колосов В.П., 20192019Шелудько Е.Г., Наумов Д.Е., Гассан Д.А., Котова О.О., Колосов В.П.Sheludko E.G., Naumov D.E., Gassan D.A., Kotova O.O., Kolosov V.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cfpd.elpub.ru/jour/article/view/187

Результаты исследований последних лет свидетельствуют о потенциальной роли гамма-аминомасляной кислоты (ГАМК), как тормозного медиатора центральной нервной системы, в патогенезе синдрома обструктивного апноэ сна (СОАС) - распространенного нарушения, часто сопутствующего бронхиальной астме (БА). Целью исследования было изучить возможную роль полиморфизмов некоторых генов ГАМКергической системы в формировании СОАС у больных БА. У 184 больных БА был выполнен ночной кардиореспираторный мониторинг для диагностики СОАС, а также проведено спирометрическое исследование с оценкой реактивности дыхательных путей на бронхолитик фенотерол. Методом LATE-ПЦР были генотипированы полиморфизмы генов GAD1 , GAD2 , GABBR1 и GABBR2 (всего 15 полиморфизмов). При ассоциативном анализе с наличием СОАС значимые результаты были получены для полиморфизма rs3749034 гена GAD1 и rs35400353 гена GABBR2 . Полиморфизм rs3749034 существенно влиял на наличие СОАС у мужчин, что сопровождалось преобладанием генотипа CC среди больных СОАС, тогда как генотипы CT+TT чаще встречались у больных без СОАС (ОШ 3,9 95%ДИ [1,36-11,67], p=0,01). При анализе в общей выборке полиморфизм GAD1 rs3749034 являлся независимым фактором, увеличивающим вероятность наличия СОАС, после коррекции на значимые конфаундеры (ОШ 1,9 95%ДИ [1,23-3,15], p=0,005). Полиморфизм rs35400353 также был ассоциирован с СОАС после коррекции на конфаундеры, хотя его взаимосвязь была менее значимой (ОШ 1,5 95%ДИ [1,1-2,3], p=0,04). Для обоих полиморфизмов отмечалась тенденция к взаимосвязи с гиперреактивностью дыхательных путей на бронхолитик: для rs3749034 - в случае CT+TT генотипов, для rs35400353 - в случае DD генотипа. Полиморфизм rs3749034 также влиял на показатели вентиляционной функции легких. При условии дополнительной верификации результатов, выявленные генетические полиморфизмы могут быть использованы для индивидуального прогнозирования риска СОАС, а также разработки персонализированных подходов в терапии БА с использованием ГАМК.

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.

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Dis. 2009; 51(4):285-293. doi: 10.1016/j.pcad.2008.08.001Alkhalil M., Schulman E.S., Getsy J. Obstructive sleep apnea syndrome and asthma: the role of continuous positive airway pressure treatment. Ann. Allergy Asthma Immunol. 2008; 101(4):350-357. doi: 10.1016/S1081-1206(10)60309-2Alkhalil M., Schulman E.S., Getsy J. Obstructive sleep apnea syndrome and asthma: the role of continuous positive airway pressure treatment. Ann. Allergy Asthma Immunol. 2008; 101(4):350-357. doi: 10.1016/S1081-1206(10)60309-2de Paula L.K., Alvim R.O., Pedrosa R.P., Horimoto A.R., Krieger J.E., Oliveira C.M., Pereira A.C., Lorenzi-Filho G. Heritability of OSA in a rural population. Chest 2016; 149(1):92-97. doi: 10.1378/chest.15-0843de Paula L.K., Alvim R.O., Pedrosa R.P., Horimoto A.R., Krieger J.E., Oliveira C.M., Pereira A.C., Lorenzi-Filho G. Heritability of OSA in a rural population. Chest 2016; 149(1):92-97. doi: 10.1378/chest.15-0843Dicpinigaitis P.V., Nierman D.M., Miller A. Baclofen-induced bronchoconstriction. Ann. Pharmacother. 1993; 27(7-8):883-884.Dicpinigaitis P.V., Nierman D.M., Miller A. Baclofen-induced bronchoconstriction. Ann. Pharmacother. 1993; 27(7-8):883-884.Dicpinigaitis P.V. Effect of the GABA-agonist baclofen on bronchial responsiveness in asthmatics. Pulm. Pharmacol. Ther. 1999; 12(4):257-260.Dicpinigaitis P.V. Effect of the GABA-agonist baclofen on bronchial responsiveness in asthmatics. Pulm. Pharmacol. Ther. 1999; 12(4):257-260.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.PA3574Dimić 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. 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Association of obstructive sleep apnea with asthma: a meta-analysis. Sci. Rep. 2017; 7(1):4088. doi: 10.1038/s41598-017-04446-6Kong 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/s41598-017-04446-6Lett 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.2016.14Lett 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.2016.14Li 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.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.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.12495Piovezan R.D., Kase C., Moizinho R., Tufik S., Poyares D. 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The authors declare that there are no conflicts of interest present.