INTERLEUKIN 1 AND INTERLEUKIN 4 GENES POLYMORPHISM ASSOCIATED WITH EARLY AND PRESCHOOL AGE CHILDREN SENSITIZATION TO STREPTOCOCCUS PYOGENES

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Abstract

Background. Streptococcus pyogenes infection and sensitization to its antigens is considered to be an unfavorable factor for the induction of rheumatic pathology. The search for genetic predictors of rheumatic diseases in general, and sensitization to S. pyogenes, in particular, is of high relevance in modern medicine.

Objective. To study the associations between interleukin 1 and interleukin 4 gene polymorphisms and the development of sensitization to antigens of S. pyogenes in toddlers and preschool children.

Materials and methods. 771 children aged 2–6 years with recurrent acute respiratory tract infections treated by allergist-immunologist and otorhinolaryngologist were included in the study. Antibodies against S. pyogenes were determined by ELISA using commercial kits “Immunoteks” (Stavropol, Russia) in all children. Children with IgG immune response to S. pyogenes were assigned to the study group (n = 306), whereas children without this response were assigned to the control group (n = 465). Both groups underwent gene typing of IL1B (+3953, C→T, rs 114634), IL1Ra (VNTR, intron 2, 89 bp) and IL4 (VNTR intron 3, 70 bp) gene polymorphisms in the Laboratory for Pharmacogenomics, ICBFM SB RAS. The data were processed using routine statistical methods for genetic analysis and the statistical software package Statistica 6.0. There were no deviations from Hardy–Weinberg equilibrium across all loci, suggesting validity of association studies between individual and combined genotypes and sensitization to antigens of S. pyogenes.

Results. Positive association between sensitization to antigens of S. pyogenes and individual genotypes have been found: IL1B (+3953, C→T)*C,T (52.6% in the study group vs. 39.8% in the control group, p = 0.001; OR = 2.02; CI(99%) 0.47–5.93), IL1Ra (VNTR, intron 2, 89 bp)*2r,5r (7.19% in the study group vs. 1.29% in the control group, p = 0.001; OR = 5.59; CI(99%) 1.58–19.77), IL4 (VNTR intron 3, 70 bp)*2r,2r (6.86% in the study group vs 3.01% in the control group, p = 0.05; OR = 2.34; CI(99%) 0.66–8.29); as well as for combined genotypes: IL1B (+3953, C→T)*C,C / IL1Ra (VNTR, intron 2, 89 bp)*2r,4r / IL4 (VNTR intron 3, 70 bp)*2r,2r (OR = 46.15); IL1B (+3953, C→T)*T,T / I-1Ra (VNTR, intron 2, 89 bp)*4r,4r / IL4 (VNTR intron 3, 70 bp)*2r,3r (OR = 8.82) and IL1B (+3953, C→T)*C,T / IL1Ra (VNTR, intron 2, 89 bp)*2r,2r / IL4 (VNTR intron 3, 70 bp)*3r,3r (OR = 7.23). Conclusion. High odds ratio (OR = 46.15) for IL1B (+3953, C→T)*C,C / IL1Ra (VNTR, intron 2, 89 bp)*2r,4r / IL4 (VNTR intron 3, 70 bp)*2r,2r suggests that combined genotype is a main marker of sensitivity and impaired immune tolerance to S. pyogenes in toddlers and preschool children. Thus, this study has confirmed the association between gene polymorphisms, and pro-inflammatory and proallergic cytokines, and autoimmune and allergic diseases.

About the authors

A. V. Shabaldin

Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation

Author for correspondence.
Email: weit2007@ya.ru

PhD, MD (Medicine), Lead Research of Laboratory of Cellular Technologies, Scientific Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russian Federation 650002, Russian Federation, Kemerovo, Sosnovy blvd., 6, Phone: +7 (3842) 39-64-29 (office); +7 951 163-90-11 (mobile).

Russian Federation

E. V. Shabaldina

Kemerovo State Medical Academy, Kemerovo, Russian Federation

Email: fake@neicon.ru

PhD (Medicine), Associate Professor, Head of the Department of Otorhinolaryngology and Clinical Immunology Kemerovo State Medical Academy, Kemerovo, Russian Federation

Russian Federation

S. V. Ryazantsev

St. Petersburg Research Institute of Ear, Throat, Nose and Speech, St. Petersburg, Russian Federation

Email: fake@neicon.ru

PhD, MD (Medicine), Professor, Deputy Director for Scientific Work St. Petersburg Research Institute of Ear, Throat, Nose and Speech, St. Petersburg, Russian Federation

Russian Federation

A. S. Simbirtsev

Research Institute of Highly Pure Biopreparations, St. Petersburg, Russian Federation

Email: fake@neicon.ru

PhD, MD (Medicine), Professor, Director of the Research Institute of Highly Pure Biopreparations, St. Petersburg, Russian Federation

Russian Federation

References

  1. Вейр Б. Анализ генетических данных: дискретные генетические признаки. М.: Мир, 1995. 213 с. [Veir B. Analiz geneticheskikh dannykh: diskretnye geneticheskie priznaki [Analysis of genetic data:discrete genetic traits]. Moscow: Mir, 1995, 215 p.
  2. Лакин Г.Ф. Биометрия. М.: Высшая школа, 1990. 352 с. [Lakin G.F. Biometriya [Biometrics]. Moscow: Vysshaja shkola, 1990, 352 p.
  3. Понасенко А.В., Головкин А.С., Шабалдин А.В., Цепокина А.В. Особенности распределения частот интронных полиморфизмов IL-1RaVNTR и IL-4VNTR при ревматических пороках митрального клапана сердца у европеоидов Сибири // Медицинская иммунология. 2015. T. 17, № 2. С. 151–158. [Ponasenko A.V., Golovkin A.S., Shabaldin A.V., Tsepokina A.V. Frequency distribution of intronic polymorphisms of IL-1raVNTR and IL-4VNTR in rheumatic mitral valve disease in caucasian population of Siberia. Meditsinskaya immunologiya = Medical Immunology (Russia), 2015, vol. 17, no. 2, pp. 151–
  4. doi: 10.15789/1563-0625-2015-2-151-158 (In Russ.)]
  5. Реброва О.Ю. Статистический анализ медицинских данных: применение пакета прикладных программ STATISTICА. М.: Медиа Сфера, 2002. 304 с. [Rebrova O.Yu. Statisticheskii analiz meditsinskikh dannykh: primenenie paketa prikladnykh programm STATISTICA [Statistical analysis of medical data: the use of the application package STATISTICA]. Moscow: Media Sfera, 2002, 304 p.
  6. Симбирцев А.С. Роль цитокинов в регуляции эмбрионального развития и формировании первичных иммунодефицитов // Российский иммунологический журнал. 2005. Т. 9, № 2. С. 12–14. [Simbirtsev A.S. The role of cytokines in the regulation of embryonic development and the formation of primary immunodeficiencies. Rossiiskii immunologi cheskii zhurnal = Russian Immunological Journal, 2005, vol. 9, no. 2, pp. 12–14. (In Russ.)]
  7. Шабалдина Е.В., Шабалдин А.В., Тюменев А.В., Рязанцев С.В., Симбирцев А.С. Сенсибилизация к Streptococcus pyogenes у детей раннего и дошкольного возраста с рецидивирующими острыми респираторными инфекциями – предиктор ревматической патологии // Инфекция и иммунитет. 2015. Т. 5, № 2. С. 157–164. [Shabaldina E.V., Shabaldin A.V., Tyumenev A.V., Ryazantsev S.V., Simbirtsev A.S. Sensitization to Streptococcus pyogenes at children of early and preschool age with recurrent respiratory infections — predictors of rheumatic pathology. Infektsiya i immunitet = Russian Journal of Infection and Immunity, 2015, vol. 5, no. 2, pp. 157–164. doi: 10.15789/2220-7619-2015-2-157-164 (In Russ.)]
  8. Arend W.P., Malyak M., Guthridge C.J. Interleukin-1 receptor antagonist: role in biology. Annu. Rev. Immunol., 1998, vol. 16, pp. 27–55.
  9. Asensi V., Rego C., Montes A.H., Collazos J., Carton J.A., Castro M.G., Alvarez V., Fernández C., Maradona J.A., Valle-Garay E. IL-1beta (+3954C/T) polymorphism could protect human immunodeficiency virus (HIV)-infected patients on highlyactive antiretroviral treatment (HAART) against lipodystrophic syndrome. Genet. Med., 2008, vol. 10, no. 3, pp. 215–223. doi: 10.1097/GIM.0b013e3181632713
  10. Auron P.E. The interleukin 1 receptor: ligand interactions and signal transduction. Cytokine Growth Factor. Rev.,1998, vol. 9, no. 3–4, pp. 221–237.
  11. Bellamy R., Ruwende C., Corrah T., McAdam K.P., Whittle H.C., Hill A.V. Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis. Tuber. Lung Dis., 1998, vol. 79, no. 2, pp. 83–89.
  12. Breit S., Steinhoff M., Blaser K., Heusser C.H., Sebald W., Levine A.D., Röcken M. A strict requirement of interleukin-4 for interleukin-4 induction in antigen-stimulated human memory T cells. Eur. J. Immunol., 1996, vol. 26, no. 8, pp. 1860–1865.
  13. Chakravorty M., Ghosh A., Choudhury A., Santra A., Hembrum J., Roychoudhury S. Ethnic differences in allele distribution for the IL8 and IL1B genes in populations from eastern India. Hum. Biol., 2004, vol. 76, no. 1, pp. 153–159.
  14. Chakravorty M., Ghosh A., Choudhury A., Santra A., Hembrum J., Roychoudhury S. Interaction between IL1B gene promoter polymorphisms in determining susceptibility to Helicobacter pylori associated duodenal ulcer. Hum. Mutat., 2006, vol. 27, no. 5, pp. 411–419.
  15. Dale J.B., Niedermeyer Sh.E., Agbaosi T., Hysmith N.D., Penfound Th.A., Hohn Cl.M., Pullen M., Bright M.I., Murrell D.S., Shenep L.E., Courtney H.S. Protective immunogenicity of group A streptococcal M-related proteins. Clin. Vaccine Immunol., 2015, vol. 22, no. 3, pp. 344–355. doi: 10.1128/CVI.00795-14
  16. Daniel C., Repa A., Wild C., Pollak A., Pot B., Breiteneder H., Wiedermann U., Mercenier A. Modulation of allergic immune responses by mucosal application of recombinant lactic acid bacteria producing the major birch pollen allergen Bet v 1. Allergy, 2006, vol. 61, no. 7, pp. 812–819.
  17. Dinkla K., Rohde M., Jansen W.T.M., Kaplan E.L., Chhatwal G.S., Talay S.R. Rheumatic fever-associated Streptococcus pyogenes isolates aggregate collagen. J. Clin. Invest., 2003, vol. 111, no. 12, pp. 1905–1912.
  18. Genevay S., Di Giovine F.S., Perneger T.V., Silvestri T., Stingelin S., Duff G., Guerne P.A. Association of interleukin-4 and interleukin-1B gene variants with Larsen score progression in rheumatoid arthritis. Arthritis Rheum., 2002, vol. 47, no. 3, pp. 303–309.
  19. Hurme M., Santilla S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur. J. Immunol., 1998, vol. 28, no. 8, pp. 2598–2602.
  20. Lamagni Th. L., Neal Sh., Keshishian C., Alhaddad N., George R., Duckworth G., Vuopio-Varkila J., Efstratiou A. Severe Streptococcus pyogenes infections, United Kingdom, 2003–2004. Emerg. Infect. Dis., 2008, vol. 14, no. 2, pp. 201–209. doi: 10.3201/eid1402.070888.
  21. Luca-Harari B., Darenberg J., Neal Sh., Siljander T., Strakova L., Tanna A., Creti R., Ekelund K., Koliou M., Tassios P.T., Van der Linden M., Straut M., Vuopio-Varkila J., Bouvet A., Efstratiou A., Schalén C., Henriques-Normark B., Strep-EURO Study Group, Jasir A. Clinical and microbiological characteristics of severe Streptococcus pyogenes disease in Europe. J. Clin. Microbiol., 2009, vol. 47, no. 4, pp. 1155–1165. doi: 10.1128/JCM.02155-08
  22. Luckey T.D. Overview of gastrointestinal microecology. Nahrung, 1987, vol. 31, no. 5–6, pp. 359–364.
  23. Mao X.Q., Kawai M., Yamashita T., Enomoto T., Dake Y., Sasaki S., Kataoka Y., Fukuzumi T., Endo K., Sano H., Aoki T., Kurimoto F., Adra C.N., Shirakawa T., Hopkin J.M. Imbalance production between interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) in bronchial asthma. Biochem. Biophys. Res. Commun., 2000, vol. 276, no. 2, pp. 607–612.
  24. Mead Ph.B. Vaginal-rectal colonization with group A streptococci in late pregnancy. Infect. Dis. Obstet. Gynecol., 2000, vol. 8, no. 5–6, pp. 217–219.
  25. Moravej A., Rasouli M., Kalani M., Asaei S., Kiany S., Najafipour S., Koohpayeh A., Abdollahi A. IL-1b (–511T/C) gene polymorphism not IL-1b (+3953T/C) and LT-a (+252A/G) gene variants confers susceptibility to visceral leishmaniasis. Mol. Biol. Rep., 2012, vol. 39, no. 6, pp. 6907–6914. doi: 10.1007/s11033-012-1517-z
  26. Mout R., Willemze R., Landegent J.E. Repeat polymorphisms in the interleukin-4 gene (IL4). Nucleic Acids Res., 1991, vol. 19, no. 13:3763.
  27. Nei M. Genetic distance between populations. Amer. Nat., 1972, vol. 106, pp. 283–292.
  28. Pearce N. What does the odds ratio estimate in a case-control study? Int. J. Epidemiol., 1993, vol. 22, no. 6, pp. 1189–1192.
  29. Pociot F., Mølvig J., Wogensen L., Worsaae H., Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur. J. Clin. Invest., 1992, vol. 22, no. 6, pp. 396–402.
  30. Rasouli M., Kiany S. Association of interferon-gamma and interleukin-4 gene polymorphisms with susceptibility to brucellosis in Iranian patients. Cytokine, 2007, vol. 38, no. 1, pp. 49–53.
  31. Santtila S., Savinainen K., Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand. J. Immunol.,1998, vol. 47, no. 3, pp. 195–198.
  32. Vamvakopoulos J.E. The interleukin-1 receptor antagonist gene: a single-copy variant of the intron 2 variable number tandem repeat (VNTR) polymorphism. Eur. J. Immunogenet., 2002, vol. 29, no. 4, pp. 337–340.
  33. Witkin S.S., Gerber W.J. Ledger influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin. Infect. Dis., 2002, vol. 34, no. 2, pp. 204–209.
  34. Yagupsky P., Landau D., Beck A., Dagan R. Carriage of Streptococcus pyogenes among infants and toddlers attending day-care facilities in closed communities in southern Israel. Eur. J. Clin. Microbiol Infect. Dis., 1995, vol. 14, no. 1, pp. 54–58.

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