Association of polymorphisms of NO synthases and arginase genes, clinical, laboratory and functional indicators with the level of nitrogen oxide in exhaled air in children with bronchial asthma
https://doi.org/10.21508/1027-4065-2019-64-5-55-68
Abstract
The article presents the results of a study of the associations of NO synthase and arginase genes in children with bronchial asthma with clinical, laboratory and functional parameters depending on the level of nitrogen oxide in exhaled air (FeNO). We examined 107 children with bronchial asthma, they were divided into 2 groups depending on the level of FeNO. We found a number of associations in the group of patients with an elevated level of FeNO (≥20 ppb): carriage of alleles and genotypes containing short tandem repeats of S (9–11) NOS1(AAT)n gene, with an early debut and severe course of the disease, an increased level of total IgE in blood serum; carriage of alleles and genotypes containing long tandem repeats L (12–16) of the NOS2A(CCTTT) n gene, with a moderate course of the disease, with an increased level of IgE; carriage of the allele *A of the ARGII gene (rs3742879) with a moderate course of the disease; carriage of the *G allele and heterozygous *AG genotype of the ARGII gene (rs3742879) with a decreased level of FEV1/FVC; carriage of L alleles and a combination of the SL and LL genotypes of the NOS1(AAT)n gene with elevated blood eosinophils (eosinophilia); a combination of S/L + L/L genotypes of the NOS1(AAT)n gene with fungal sensitization. The authors established the correlations between disease severity and NOS1(AAT)n; the age of the manifestation of the disease and NOS1(AAT)n; FEV1/FVC and ARGII (rs3742879); feedback between blood eosinophilia and NOS1(AAT)n. The authors also determined a number of associations in the group of patients with low level of FeNO (<20 ppb): carriage of alleles and genotypes containing short tandem repeats of S (9–11) gene NOS1(AAT)n, with fungal sensitization; carriage of alleles and genotypes containing long tandem repeats of L (12–16) gene NOS2A(CCTTT)n, with reduced FEV1 and FEV1/FVC; carriage of the homozygous genotype of *GG gene ARGII(rs3742879) with epidermal sensitization. With a reduced level of FeNO, the study determined a relationship between the severity of bronchial asthma and NOS1(AAT)n; degree of effectiveness of anti-inflammatory basic therapy and NOS1(AAT)n; fungal sensitization and NOS1(AAT)n; feedback between FEV1 and NOS2(CCTTT)n; FEV1/FVC and NOS2(CCTTT)n.
About the Authors
B. T. BatozhargalovaRussian Federation
Moscow
S. E. Diakova
Russian Federation
Moscow
N. V. Petrova
Russian Federation
Moscow
Yu. L. Mizernitsky
Russian Federation
Moscow
R. A. Zinchenko
Russian Federation
Moscow
References
1. Мизерницкий Ю.Л., Цыпленкова С.Э., Мельникова И.М. Современные методы оценки функционального состояния бронхолегочной системы у детей. М.: МЕДПРАК- ТИКА-М, 2012; 176. [Mizernitsky Yu.L., Tsyplenkova S.E., Mel’nikova I.M. Modern methods of assessing the functional state of the bronchopulmonary system in children. M.: MEDPRAKTIKA-M, 2012;176 (in Russ.)]
2. Petsky H.L., Kew K.M., Chang A.B. Review Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Systematic Reviews. 2016; Issue 11. Art. NO.: CD011439.
3. Dweik R.A., Boggs P.B., Erzurum S.C., Irvin C.G., Leigh M.W., Lundberg J.O. et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FeNO) for clinical applications. Am J Respir Crit Care Med 2011; 184(5): 602–615. DOI: 10.1164/rccm.9120-11ST
4. Barnes P.J., Dweik R.A., Gelb A.F., Gibson P.G., George S.C., Grasemann H. et al. Exhaled nitric oxide in pulmonary diseases: a comprehensive review. Chest 2010; 138(3): 682–692. DOI: 10.1378/chest.09-2090
5. Rao D.R., Phipatanakul W. An Overview of Fractional Exhaled Nitric Oxide and Children with Asthma. Expert Rev. Clin Immunol 2016; 12(5): 521–530. DOI: 10.1586/1744666X.2016.1141049
6. Wechsler M.E., Grasemann H., Deykin A., Silverman E.K., Yandava C.N., Israel E. et al. Exhaled nitric oxide in patients with asthma: association with NOS1 genotype. Am J Respir Crit Care Med 2000; 162(6): 2043–2047.
7. Xu W., Comhair S.A.A., Janocha A.J., Lara A., Mavrakis L.A., Bennett C.D. et al. Arginine metabolic endotypes related to asthma severity. PLoS One 2017; 12(8): e0183066. DOI: 10.1371/journal.pone.0183066
8. Hirai K., Shirai T., Suzuki M., Shimomura T., Itoh K. Association between ( CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations. J Allergy Clin Immunol 2018; 142(2): 663–665. DOI: 10.1016/j.jaci.2018.02.023
9. Sato S., Wang X., Saito J., Fukuhara А., Uematsu M., Suzuki Y. et al. Exhaled nitric oxide and inducible nitric oxide synthase gene polymorphism in Japanese asthmatics. Allergol Internat 2016; 65(3): 300–305. DOI: 10.1016/j.alit.2016.02.007
10. Salam M.T., Bastain T.M., Rappaport E.B., Islam T., Berhane K., Gauderman W.J. et al. Genetic variations in nitric oxide synthase and arginase influence exhaled nitric oxide levels in children. Allergy 2011; 66(3): 412–419. DOI: 10.1111/j.1398-9995.2010.02492.x
11. Brindicci C., Ito K., Barnes P.J., Kharitonov S.A. Differential flow analysis of exhaled nitric oxide in patients with asthma of differing severity. Chest 2007; 131(5): 1353–1362. DOI: 10.1378/chest.06-2531
12. Warpeha K.M., Xu W., Liu L. Charles I.G., Patterson C.C., Ah-Fat F. et al. Genotyping and functional analysis of a polymorphic (CCTTT) (n) repeat of NOS2A in diabetic retinopathy. FASEB J 1999; 13(13): 1825–1832.
13. Maarsingh H., Leusink J., Bos I.S., Zaagsma J., Meurs H. Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma. Respir Res 2006; 7(1): 6. DOI: 10.1186/1465-9921-7-6
14. Maarsingh H., Zaagsma J., Meurs H. Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives. British J Pharmacol 2009; 158(3): 652–664. DOI: 10.1111/j.1476-5381.2009.00374.x
15. Leung T.F., Liu E.K., Tang N.L., Ko F.W., Li C.Y., Lam C.W., Wong G.W. Nitric oxide synthase polymorphisms and asthma phenotypes in Chinese children. Clin Exp Allergy 2005; 35(10): 1288–1294.
16. Spanier A.J., Kahn R.S., Hornung R.W., Wang N., Sun G., Lierl M.B. et al. Environmental Exposures, Nitric Oxide Synthase Genes, and Exhaled Nitric Oxide in Asthmatic Children. Pediatr Pulmonol 2009; 44(8): 812–819. DOI: 10.1002/ppul.21071
17. Konno S., Hizawa N., Yamaguch, E., Jinushi E., Nishimura M. (CCTTT)n repeat polymorphism in the NOS2 gene promoter is associated with atopy. J Allergy Clin Immunol 2001; 108(5): 810–814.
18. Батожаргалова Б.Ц., Мизерницкий Ю.Л., Дьякова С.Э., Петрова Н.В., Зинченко Р.А. Роль полиморфных вариантов генов NO-синтаз и аргиназы в формировании бронхиальной астмы у детей. Медицинская генетика 2017; 16(2): 40–48. [Batozhargalova B.TS., Mizernitsky Yu.L., Dyakova S.E., Petrova N.V., Zinchenko R.A. The role of polymorphic variants of NO synthases and arginase genes in the formation of bronchial asthma in children. Meditsinskaya genetika 2017; 16(2): 40–48 (in Russ.)]
19. Leung T.F., Liu E.K., Li C.Y., Chan I.H., Yung E., Lam C.W., Wong G.W. Lack of association between NOS2 pentanucleotide repeat polymorphism and asthma phenotypes or exhaled nitric oxide concentration. Pediatric Pulmol 2006; 41(7): 649–655. DOI: 10.1002/ppul.20428
20. Lee J., Ryu H., Ferrante R.J., Morris S.M.Jr., Ratan R.R. Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 2003; 100: 4843–4848.
21. Sarnelli G., Grosso M., Palumbo I., Pesce M., D’Alessandro A., Zaninotto G. et al. Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia. United Eur Gastroenterol J 2017; 5(2): 200–207. DOI: 10.1177/2050640616648870
Review
For citations:
Batozhargalova B.T., Diakova S.E., Petrova N.V., Mizernitsky Yu.L., Zinchenko R.A. Association of polymorphisms of NO synthases and arginase genes, clinical, laboratory and functional indicators with the level of nitrogen oxide in exhaled air in children with bronchial asthma. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2019;64(5):55-68. (In Russ.) https://doi.org/10.21508/1027-4065-2019-64-5-55-68