The role of polymorphic variants of arginase genes (ARG1, ARG2) involved in beta-2-agonist metabolism in the development and course of asthma

Asthma is a common severe disease of the respiratory tract, it leads to a significant impairment in the quality of a patient’s life unless effectively treated. Uncontrolled asthma symptoms are a cause of disease progression and development, they lead to an increase in the patient’s disability. The sensitivity to asthma therapy largely depends on the interaction of genetic and epigenetic factors, which account for about 50–60 % of variability of therapeutic response. Beta-2-agonists are some of the major class of bronchodilators used for asthma management. According to published data, allelic variants of the arginase ARG1 and ARG2 genes are associated with a risk of asthma development, spirometry measures and efficacy of bronchodilator therapy. High arginase activity results in a low level of plasma L-arginine and in a decrease in nitric oxide, and, as a result, in an increase in airway inflammation and remodeling. Arginase genetic polymorphisms (rs2781667 of the ARG1 gene, rs17249437, rs3742879, rs7140310 of the ARG2 gene) were studied in 236 children with asthma and 194 unrelated healthy individuals of Russian, Tatar and Bashkir ethnicity from the Republic of Bashkortostan. Association analysis of the studied polymorphisms with asthma development and course, the sensitivity to therapy in patients was carried out. It was found that the rs2781667*C allele of the ARG1 gene is a marker of an increased risk of asthma in Tatars. In Russians, the association of rs17249437*TT and rs3742879*GG genotypes of the ARG2 gene with a decrease in spirometry measures (FEV1, MEF25) was established. In Russians and Tatars receiving glucocorticoid monotherapy or combination therapy, the association of the rs17249437*T allele and rs17249437*TT genotype of the ARG2 gene with a partially controlled and uncontrolled course of asthma was shown.

asthma, beta-2-agonists, arginase 1 (ARG1), arginase 2 (ARG2), association, predisposition genes

1. Almomani B.A., Al-Eitan L.N., Al-Sawalha N.A., Samrah S.M., Al-Quasmi M.N. Association of genetic variants with level of asthma control in the Arab population. J. Asthma Allergy. 2019; 12:35-42. DOI 10.2147/JAA.S186252.

2. Bateman E.D., Kornmann O., Schmidt P., Pivovarova A., Engel M., Fabbri L.M. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J. Allergy Clin. Immunol. 2011;128(2):315-322. DOI 10.1016/j.jaci.2011.06.004.

3. Batozhargalova B.T., Mizernitski Y.L., Diakova S.E., Petrova N.V., Zinchenko R.A. Role of polymorphic variants of NO synthase and arginase genes in child bronchial asthma. Meditsinskaya Genetika = Medical Genetics. 2017;16(2):40-48. (in Russian)

4. Cloots R.H.E., Poynter M.E., Terwindt E., Lamers W.H., Köhler S.E. Hypoargininemia exacerbates airway hyperresponsiveness in a mouse model of asthma. Respir. Res. 2018;19:98. DOI 10.1186/s12931-018-0809-9.

5. Dimitriades V., Rodriguez P.C., Zabaleta J., Ochoa A.C. Arginase I levels are decreased in the plasma of pediatric patients with atopic dermatitis. Ann. Allergy Asthma Immunol. 2014;113(3): 271-275. DOI 10.1016/j.anai.2014.06.010.

6. Donthi S., Neela V.S.K., Gaddam S., Mohammed H.H., Ansari S.S., Valluri V.L., Sivasai K.S.R. Association of increased risk of asthma with elevated arginase & interleukin-13 levels in serum & rs2781666 G/T genotype of arginase I. Indian J. Med. Res. 2018;148(2):159-168. DOI 10.4103/ijmr.IJMR_379_16.

7. Drake K.A., Torgerson D.G., Gignoux C.R., Galanter J.M., Roth L.A., Huntsman S., Eng C., Oh S.S., Yee S.W., Lin L., Bustamante C.D., Moreno-Estrada A., Sandoval K., Davis A., Borrell L.N., Farber H.J., Kumar R., Avila P.C., Brigino-Buenaventura E., Chapela R., Ford J.G., Lenoir M.A., Lurmann F., Meade K., Serebrisky D., Thyne S., Rodríguez-Cintrón W., Sen S., Rodríguez-Santana J.R., Hernandez R.D., Giacomini K.M., Burchard E.G. A genome-wide assoсiation study of bronchodilator response in Latinos implicates rare variants. J. Allergy Clin. Immunol. 2014;133(2):370-378. DOI 10.1016/j.jaci.2013.06.043.

8. Duan Q.L., Du R., Lasky-Su J., Klanderman B.J., Partch A.B., Peters S.P., Irvin C.G., Hanrahan J.P., Lima J.J., Blake K.V., Liggett S.B., Litonjua A.A., Tantisira K.G. A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics. Pharmacogenomics J. 2013; 13(2):130-136. DOI 10.1038/tpj.2011.56.

9. Duan Q.L., Gaume B.R., Hawkins G.A., Himes B.E., Bleecker E.R., Klanderman B., Irvin C.G., Peters S.P., Meyers D.A., Hanrahan J.P., Lima J.J., Litonjua A.A., Tantisira K.G., Liggett S.B. Regulatory haplotypes in ARG1 are associated with altered bronchodilator response. Am. J. Respir. Crit. Care Med. 2011; 183(4):449-454. DOI 10.1164/rccm.201005-0758OC.

10. Farzan N., Vijverberg S.J., Arets H.G., Raaijmakers J.A., Maitlandvan der Zee A.H. Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: a systematic review. Clin. Exp. Allergy. 2017;47(2):271-293. DOI 10.1111/cea.12844.

11. Fedorova Yu.Yu., Karunas A.S., Murzina R.R., Mukhtarova L.A., Ramazanova N.N., Gimalova G.F., Gatiyatullin R.F., Zagidullin Sh.Z., Etkina E.I., Khusnutdinova E.K. Association study of the β2-adrenergic receptor gene polymorphisms with bronchial asthma in Russians. Prakticheskaya Meditsina = Practical Medicine. 2013;5(74):116-120. (in Russian)

12. Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2018. Vancouver, USA GINA, 2018.

13. Kim S.H., Ye Y.M., Lee H.Y., Sin H.J., Park H.S. Combined pharmacogenetic effect of ADCY9 and ADRB2 gene polymorphisms on the bronchodilator response to inhaled combination therapy. J. Clin. Pharm. Ther. 2011;36(3):399-405. DOI 10.1111/j.1365-2710.2010.01196.x.

14. Klement R.F., Zilber H.A. Functional Diagnostic Tests in Pulmonology: Guidelines. St. Petersburg, 1993. (in Russian)

15. Li H., Romieu I., Sienra-Monge J., Ramirez-Aguilar M., Estela del Rio-Navarro B., Kistner E.O., Gjessing H.K., Lara-Sanchez I. del C., Chiu G.Y., London S.J. Genetic polymorphisms in arginase I and II and childhood asthma and atopy. J. Allergy Clin. Immunol. 2006;117(1):119-126. DOI 10.1016/j.jaci.2005.09.026.

16. Litonjua A.A., Lasky-Su J., Schneiter K., Tantisira K.G., Lazarus R. ARG1 is a novel bronchodilator response gene: screening and replication in four asthma cohorts. Am. J. Respir. Crit. Care Med. 2008;178(7):688-694. DOI 10.1164/rccm.200709-1363OC.

17. Martinez F.D., Graves P.E., Baldini M., Solomon S., Erickson R. Association between genetic polymorphisms of the beta-2 adrenoceptor and response to albuterol in children with and without a history of wheezing. J. Clin. Invest. 1997;100(12):3184-3188. DOI 10.1172/JCI119874.

18. Mathew C.G.P. The isolation of high molecular weight eucariotic DNA. In: Walker J.M. (Ed.). Methods in Molecular Biology. Vol. 2. Nucleic Acids. Humana Press, Clifton, New Jersey, 1984;31-34.

19. Meurs H., Zaagsma J., Maarsingh H., Duin M. Recent patents in allergy/immunology: use of arginase inhibitors in the treatment of asthma and allergic rhinitis. Allergy. 2019;74(6):1206-1208. DOI 10.1111/all.13770.

20. National Program “Bronchial Asthma in Children. Treatment Strategy and Prevention”. 4th edn. Moscow: Original-Maket Publ., 2012. (in Russian)

21. National Program “Bronchial Asthma in Children. Treatment Strategy and Prevention”. 5th edn. Moscow: Original-Maket Publ., 2017. (in Russian)

22. Poon A.H., Tantisira K.G., Litonjua A.A., Lazarus R., Xu J., LaskySu J., Lima J.J., Irvin C.G., Hanrahan J.P., Lange C., Weiss S.T. Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma. Pharmacogenet. Genomics. 2008;18(5):373-382. DOI 10.1097/FPC.0b013e3282fa760a.

23. Said A.M.A., Naqshbandi A.A.A., Amin Y.K., Ali R.J. Association of the arginase Ι with bronchial asthma. J. Univ. Babylon Pure Appl. Sci. 2019;27(2):238-243. DOI 10.29196/jubpas.v27i2.2092.

24. Salam M.T., Islam T., Gauderman W.J., Gilliland F.D. Roles of arginase variants, atopy, and ozone in childhood asthma. J. Allergy Clin. Immunol. 2009;123:596-602. DOI 10.1016/j.jaci.2008.12.020.

25. Scaparrotta A., Franzago M., Loredana Marcovecchio M., Pillo S.D., Chiarelli F., Mohn A., Stuppia L. Role of THRB, ARG1, and ADRB2 genetic variants on bronchodilators response in asthmatic children. J. Aerosol. Med. Pulm. Drug Deliv. 2019;32: 1-10. DOI 10.1089/jamp.2018.1493.

26. Vonk J.M., Postma D.S., Maarsingh H., Bruinenberg M., Koppelman G.H., Meurs H. Arginase 1 and arginase 2 variations associate with asthma, asthma severity and β2 agonist and steroid response. Pharmacogenet. Genomics. 2010;20(3):179-186. DOI 10.1097/FPC.0b013e328336c7fd.