medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.1234/XXXX-XXXX-2016-1-27-36medgen-89Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHИсследование роли полиморфных вариантов генов, ответственных за метаболизм глюкокортикостероидов, в развитии бронхиальной астмыRole of polymorphisms of genes involved in glucocorticoid metabolism in the risk of bronchial asthmaФедороваЮ. Ю.FedorovaY. Y.molgen@anrb.ruКарунасА. С.KarunasA. S.noemail@neicon.ruМурзинаР. Р.MurzinaR. R.noemail@neicon.ruГималоваГ. Ф.GimalovaG. F.noemail@neicon.ruГатиятуллинР. Ф.GatiyatullinR. F.noemail@neicon.ruЭткинаЭ. И.EtkinaE. I.noemail@neicon.ruХуснутдиноваЭ. К.KhusnutdinovaE. K.noemail@neicon.ruФГБУН Институт биохимии и генетики Уфимского научного центра Российской академии наукRussian FederationФГБУН Институт биохимии и генетики Уфимского научного центра Российской академии наук; «Башкирский государственный университет»Russian Federation«Башкирский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииRussian Federation2016071020161512736Copyright © Федорова Ю.Ю., Карунас А.С., Мурзина Р.Р., Гималова Г.Ф., Гатиятуллин Р.Ф., Эткина Э.И., Хуснутдинова Э.К., 20162016Федорова Ю.Ю., Карунас А.С., Мурзина Р.Р., Гималова Г.Ф., Гатиятуллин Р.Ф., Эткина Э.И., Хуснутдинова Э.К.Fedorova Y.Y., Karunas A.S., Murzina R.R., Gimalova G.F., Gatiyatullin R.F., Etkina E.I., Khusnutdinova E.K.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/89

Бронхиальная астма (БА) является одним из наиболее распространенных тяжелых и инвалидизирующих многофакторных заболеваний. Проведен анализ полиморфных вариантов генов глюкокортикоидного рецептора NR3C1 ( rs41423247 ), рецептора кортикотропин-рилизинг гормона CRHR1 ( rs242939, rs1876828, rs242941 ) и транскрипционного фактора TBX21 ( rs2240017 ) у больных бронхиальной астмой, находящихся на терапии глюкокортикостероидами, и здоровых индивидов, проживающих на территории Республики Башкортостан (РБ). Установлена ассоциация полиморфного варианта rs41423247 гена NR3C1 со значительным снижением показателей функции внешнего дыхания у больных БА. Обнаружено, что у башкир маркерами повышенного риска развития БА являются генотип rs242941*C/A и гаплотип AA ( rs242939, rs242941 ) гена CRHR1 ; у татар - генотип rs41423247*С/G гена NR3C1 .

Bronchial asthma is one of the most common severe and disabling multifactorial diseases. The association analysis of polymorphisms of glucocorticoid receptor gene NR3C1 ( rs41423247 ), corticotropin-releasing hormone receptor 1 gene CRHR1 ( rs242939, rs1876828, rs242941 ), T-box transcription factor gene TBX21 ( rs2240017 ) in asthmatic patients treated with corticosteroids and unrelated healthy from Bashkortostan Republic was performed. The association of NR3C1 polymorphism rs41423247 with decline in lung functions in patients has been revealed. The genotype rs242941*C/A and haplotype AA ( rs242939, rs242941 ) of gene CRHR1 were significantly associated with BA in Bashkirs, while the genotype rs41423247*С/G of gene NR3C1 was associated with BA in Tatars.

бронхиальная астмаполиморфный вариантгеныответственные за метаболизм глюкокортикостероидовассоциацияbronchial asthmapolymorphismgenes involved in glucocorticoid metabolismassociationReferencesGINA Report, Global Strategy for Asthma Management and Prevention. - 2015. - P. 1-149.GINA Report, Global Strategy for Asthma Management and Prevention. - 2015. - P. 1-149.Van Rossum E.F.C., Lamberts S.W.J. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition // Recent Progress in Hormone Research Journal. - 2004. - Vol. 59. - P. 333-357.Van Rossum E.F.C., Lamberts S.W.J. Polymorphisms in the glucocorticoid receptor gene and their associations with metabolic parameters and body composition // Recent Progress in Hormone Research Journal. - 2004. - Vol. 59. - P. 333-357.Portelli M., Sayers I. Genetic basis for personalized medicine in asthma // Expert Rev. Respir. Med. - 2012. - Vol. 6(2). - P. 223-236.Portelli M., Sayers I. Genetic basis for personalized medicine in asthma // Expert Rev. Respir. Med. - 2012. - Vol. 6(2). - P. 223-236.Ortega V.E., Meyers D.A., Bleecker E.R. Asthma pharmacogenetics and the development of genetic profiles for personalized medicine // Pharmgenomics Pers. Med. - 2015. - Vol. 8. - P. 9-22.Ortega V.E., Meyers D.A., Bleecker E.R. Asthma pharmacogenetics and the development of genetic profiles for personalized medicine // Pharmgenomics Pers. Med. - 2015. - Vol. 8. - P. 9-22.Fleury I., Beaulieu P., Primeau M. et al. Characterization of the BclI polymorphism in the glucocorticoid receptor gene // Clin. Chem. - 2003. - Vol. 49(9). - P. 1529-1531.Fleury I., Beaulieu P., Primeau M. et al. Characterization of the BclI polymorphism in the glucocorticoid receptor gene // Clin. Chem. - 2003. - Vol. 49(9). - P. 1529-1531.Szalai C., Ungvаri I., Pelyhe L. et al. Asthma from a pharmacogenomic point of view // Br. J. Pharmacol. - 2008. - Vol. 153(8). - P. 1602-1614.Szalai C., Ungvаri I., Pelyhe L. et al. Asthma from a pharmacogenomic point of view // Br. J. Pharmacol. - 2008. - Vol. 153(8). - P. 1602-1614.Stevens A., Ray D.W., Zeggini E. et al. Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype // J. Clin. Endocrinol. Metab. - 2004. - Vol. 89(2). - P. 892-897.Stevens A., Ray D.W., Zeggini E. et al. Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype // J. Clin. Endocrinol. Metab. - 2004. - Vol. 89(2). - P. 892-897.Жданова М.В., Богданова М.А., Войтович А.Н. и др. Особенности течения бронхиальной астмы у детей с различными генотипами BclI-полиморфизма гена глюкокортикоидного рецептора // Педиатрия. - 2007. - Т. 86(4). - С. 19-24. Zhdanova M.V., Bogdanova M.A., Voytovich A.N. i dr. Osobennosti techeniya bronkhial’noy astmy u detey s razlichnymi genotipami BclI-polimorfizma gena glyukokortikoidnogo retseptora // Pediatriya. - 2007. - Vol. 86(4). - P. 19-24.Жданова М.В., Богданова М.А., Войтович А.Н. и др. Особенности течения бронхиальной астмы у детей с различными генотипами BclI-полиморфизма гена глюкокортикоидного рецептора // Педиатрия. - 2007. - Т. 86(4). - С. 19-24. Zhdanova M.V., Bogdanova M.A., Voytovich A.N. i dr. Osobennosti techeniya bronkhial’noy astmy u detey s razlichnymi genotipami BclI-polimorfizma gena glyukokortikoidnogo retseptora // Pediatriya. - 2007. - Vol. 86(4). - P. 19-24.Pietras T., Panek M., Tworek D. et al. The Bcl I single nucleotide polymorphism of the human glucocorticoid receptor gene h-GR/NR3C1 promoter in patients with bronchial asthma: pilot study // Mol. Biol. Rep. - 2011. - Vol. 38. - P. 3953-3958.Pietras T., Panek M., Tworek D. et al. The Bcl I single nucleotide polymorphism of the human glucocorticoid receptor gene h-GR/NR3C1 promoter in patients with bronchial asthma: pilot study // Mol. Biol. Rep. - 2011. - Vol. 38. - P. 3953-3958.Panek M., Pietras T., Szemraj J. et al. Association analysis of the glucocorticoid receptor gene (NR3C1) haplotypes (ER22/23EK, N363S, BclI) with mood and anxiety disorders in patients with asthma // Exp. Ther. Med. - 2014. - Vol. 8. - P. 662-670.Panek M., Pietras T., Szemraj J. et al. Association analysis of the glucocorticoid receptor gene (NR3C1) haplotypes (ER22/23EK, N363S, BclI) with mood and anxiety disorders in patients with asthma // Exp. Ther. Med. - 2014. - Vol. 8. - P. 662-670.Szczepankiewicz A., Brеborowicz A., Sobkowiak P. et al. No association of glucocorticoid receptor polymorphisms with asthma and response to glucocorticoids // Adv. Med. Sci. - 2008. - Vol. 53(2). - P. 245-250.Szczepankiewicz A., Brеborowicz A., Sobkowiak P. et al. No association of glucocorticoid receptor polymorphisms with asthma and response to glucocorticoids // Adv. Med. Sci. - 2008. - Vol. 53(2). - P. 245-250.Panek M., Pietras T., Fabijan A. et al. Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes // Exp. Ther. Med. - 2013. - Vol. 5. - P. 572-580.Panek M., Pietras T., Fabijan A. et al. Effect of glucocorticoid receptor gene polymorphisms on asthma phenotypes // Exp. Ther. Med. - 2013. - Vol. 5. - P. 572-580.Tantisira K.G., Lake S., Silverman E.S. et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids // Hum. Mol. Genet. - 2004. - Vol. 13(13). - P. 1353-1359.Tantisira K.G., Lake S., Silverman E.S. et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids // Hum. Mol. Genet. - 2004. - Vol. 13(13). - P. 1353-1359.Tsartsali L., Papadopoulos M., Lagona E. et al. Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids // Neuroimmunomodulation. - 2012. - Vol. 19(2). - P. 88-95.Tsartsali L., Papadopoulos M., Lagona E. et al. Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids // Neuroimmunomodulation. - 2012. - Vol. 19(2). - P. 88-95.Awasthi S., Gupta S., Agarwal S. et al. CRHR1 gene SNPs and response to systemic corticosteroids in Indian asthmatic children during acute exacerbation // Indian J. Pediatr. - 2015. - Vol. 82(9). - P. 781-786.Awasthi S., Gupta S., Agarwal S. et al. CRHR1 gene SNPs and response to systemic corticosteroids in Indian asthmatic children during acute exacerbation // Indian J. Pediatr. - 2015. - Vol. 82(9). - P. 781-786.Kim W.J., Sheen S.S., Kim T.-H. et al. Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD // Respirology. - 2009. - Vol. 14. - P. 260-263.Kim W.J., Sheen S.S., Kim T.-H. et al. Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD // Respirology. - 2009. - Vol. 14. - P. 260-263.Dijkstra A., Koppelman G.H., Vonk J.M. et al. Pharmacogenomics and outcome of asthma: no clinical application for long-term steroid effects by CRHR1 polymorphisms // J. Allergy Clin. Immunol. - 2008. - Vol. 121(6). - P. 1510-1513.Dijkstra A., Koppelman G.H., Vonk J.M. et al. Pharmacogenomics and outcome of asthma: no clinical application for long-term steroid effects by CRHR1 polymorphisms // J. Allergy Clin. Immunol. - 2008. - Vol. 121(6). - P. 1510-1513.Drolet G., Rivest S. Corticotropin-releasing hormone and its receptors; an evaluation at the transcription level in vivo // Peptides. - 2001. - Vol. 22. - P. 761-767.Drolet G., Rivest S. Corticotropin-releasing hormone and its receptors; an evaluation at the transcription level in vivo // Peptides. - 2001. - Vol. 22. - P. 761-767.Raby B.A., Hwang E.-S., Steen K.V. et al. T-Bet polymorphisms are associated with asthma and airway hyperresponsiveness // Am. J. Respir. Crit. Care Med. - 2006. - Vol. 173. - P. 64-70.Raby B.A., Hwang E.-S., Steen K.V. et al. T-Bet polymorphisms are associated with asthma and airway hyperresponsiveness // Am. J. Respir. Crit. Care Med. - 2006. - Vol. 173. - P. 64-70.Tantisira K.G., Hwang E.S., Raby B.A. et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids // Proc. Natl. Acad. Sci. USA. - 2004. - Vol. 101(52). - P. 18099-18104.Tantisira K.G., Hwang E.S., Raby B.A. et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids // Proc. Natl. Acad. Sci. USA. - 2004. - Vol. 101(52). - P. 18099-18104.Ye Y.M., Lee H.Y., Kim S.H. еt al. Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment // J. Clin. Pharm. Ther. - 2009. - Vol. 34. - P. 693-701.Ye Y.M., Lee H.Y., Kim S.H. еt al. Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment // J. Clin. Pharm. Ther. - 2009. - Vol. 34. - P. 693-701.Tantisira K.G., Lasky-Su J., Harada M. et al. Genomewide Association between GLCCI1 and response to glucocorticoid therapy in asthma // N. Engl. J. Med. - 2011. - Vol. 365(13). - P. 1173-1183.Tantisira K.G., Lasky-Su J., Harada M. et al. Genomewide Association between GLCCI1 and response to glucocorticoid therapy in asthma // N. Engl. J. Med. - 2011. - Vol. 365(13). - P. 1173-1183.Tantisira K.G., Damask A., Szefler S.J. et al. Genome-wide association identifies the T Gene as a novel asthma pharmacogenetic locus // Am. J. Respir. Crit. Care Med. - 2012. - Vol. 185(12). - P. 1286-1291.Tantisira K.G., Damask A., Szefler S.J. et al. Genome-wide association identifies the T Gene as a novel asthma pharmacogenetic locus // Am. J. Respir. Crit. Care Med. - 2012. - Vol. 185(12). - P. 1286-1291.Himes B.E., Jiang X., Hu R. et al. Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene // PLoS Genetics. - 2012. - Vol. 8(7). - e1002824.Himes B.E., Jiang X., Hu R. et al. Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene // PLoS Genetics. - 2012. - Vol. 8(7). - e1002824.Duan Q.L., Lasky-Su J., Himes B.E. et al. A genome-wide association study of bronchodilator response in asthmatics // Pharmacogenomics J. - 2014. - Vol. 14(1). - P. 41-47.Duan Q.L., Lasky-Su J., Himes B.E. et al. A genome-wide association study of bronchodilator response in asthmatics // Pharmacogenomics J. - 2014. - Vol. 14(1). - P. 41-47.Dahlin A., Litonjua A., Lima J.J. et al. Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in asthma // PLoS One. - 2015. - Vol. 10(6). - e0129385.Dahlin A., Litonjua A., Lima J.J. et al. Genome-wide association study identifies novel pharmacogenomic loci for therapeutic response to montelukast in asthma // PLoS One. - 2015. - Vol. 10(6). - e0129385.Под ред. Чучалина А.Г. Национальная программа «Бронхиальная астма у детей. Стратегия лечения и профилактика». - М.: Атмосфера, 2008. - 108 с. Pod red. Chuchalina A.G. Natsional’naya programma «Bronkhial’naya astma u detey. Strategiya lecheniya i profilaktika». - M.: Atmosfera, 2008 - 108 с.Под ред. Чучалина А.Г. Национальная программа «Бронхиальная астма у детей. Стратегия лечения и профилактика». - М.: Атмосфера, 2008. - 108 с. Pod red. Chuchalina A.G. Natsional’naya programma «Bronkhial’naya astma u detey. Strategiya lecheniya i profilaktika». - M.: Atmosfera, 2008 - 108 с.Клемент Р.Ф., Зильбер H.A. Функционально-диагностические исследования в пульмонологии: Методические рекомендации. - СПб., 1993. - 43 с. Klement RF, Zil’ber HA. Funktsional’no-diagnosticheskie issledovaniya v pul’monologii: metodicheskie rekomendatsii. - S-Pb., 1993. - 43 с.Клемент Р.Ф., Зильбер H.A. Функционально-диагностические исследования в пульмонологии: Методические рекомендации. - СПб., 1993. - 43 с. Klement RF, Zil’ber HA. Funktsional’no-diagnosticheskie issledovaniya v pul’monologii: metodicheskie rekomendatsii. - S-Pb., 1993. - 43 с.Mathew C.C. The isolation of high molecular weight eucariotic DNA // Methods Mol. Med. - 1984. - Vol. 2. - P. 31-34.Mathew C.C. The isolation of high molecular weight eucariotic DNA // Methods Mol. Med. - 1984. - Vol. 2. - P. 31-34.Rozen S, Skaletsky HJ. Primer3 on the WWW for general users and for biologist programmers // Methods Mol. Biol. - 2000. - Vol. 132. - P. 365-366.Rozen S, Skaletsky HJ. Primer3 on the WWW for general users and for biologist programmers // Methods Mol. Biol. - 2000. - Vol. 132. - P. 365-366.Barrett J.C., Fry B., Maller J. et al. Haploview: analysis and visualization of LD and haplotype maps // Bioinformatics. - 2005. - Vol. 21(2). - P. 263-265.Barrett J.C., Fry B., Maller J. et al. Haploview: analysis and visualization of LD and haplotype maps // Bioinformatics. - 2005. - Vol. 21(2). - P. 263-265.Lou X.-Y., Chen G.-B., Yan L. et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence // Am. J. Hum. Genet. - 2007. - Vol. 80. - P. 1125-1135.Lou X.-Y., Chen G.-B., Yan L. et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence // Am. J. Hum. Genet. - 2007. - Vol. 80. - P. 1125-1135.Sharma N., Awasthi S., Phadke S.R. A novel genotyping method for detection of the CRHR1 (rs1396862: C>T) gene variation among North Indian population // Mol. Biol. Rep. - 2014. - Vol. 41(5). - P. 2809-2813.Sharma N., Awasthi S., Phadke S.R. A novel genotyping method for detection of the CRHR1 (rs1396862: C>T) gene variation among North Indian population // Mol. Biol. Rep. - 2014. - Vol. 41(5). - P. 2809-2813.Finotto S., Neurath M.F., Glickman J.N. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet // Science. - 2002. - Vol. 295. - P. 336-338.Finotto S., Neurath M.F., Glickman J.N. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet // Science. - 2002. - Vol. 295. - P. 336-338.

The authors declare that there are no conflicts of interest present.