Ассоциация полиморфных маркеров генов-кандидатов с риском манифестации эндокринной офтальмопатии у пациентов с болезнью Грейвса

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Аннотация

Цель исследования – анализ ассоциации полиморфных маркеров генов CTLA4, TNF, IL10 и IL16 с риском манифестации эндокринной офтальмопатии (ЭОП) у пациентов с болезнью Грейвса (БГ).
Материалы и методы. В исследование типа случай-контроль включено 248 пациентов с БГ. Методом полимеразной цепной реакции изучено распределение аллелей и генотипов полиморфных маркеров A60G (rs3087243) гена CTLA4, G(-308)А (rs1800629) гена TNF, G(-1082)A (rs1800896) гена IL10, T3249C (rs4778641) гена IL16 среди 141 пациента с болезнью Грейвса и ЭОП и 107 пациентов с БГ, не имеющих ЭОП.
Результаты и обсуждение. У пациентов с БГ и ЭОП достоверно повышены частоты встречаемости аллелей А и генотипов АА и снижена доля аллелей G и генотипа GG полиморфных маркеров rs3087243 гена CTLA4 и rs1800896 гена IL10, а также генотипа GG полиморфного маркера rs1800629 гена TNF. Полиморфизм гена CTLA4 также ассоциировался с активностью и тяжестью ЭОП. Сравнительный анализ частот аллелей и генотипов полиморфного маркера гена IL16 не показал достоверных различий.
Заключение. Риск манифестации и течение ЭОП у пациентов с БГ могут быть обусловлены не только средовыми, но и генетическими факторами риска.

Ключевые слова: болезнь Грейвса, эндокринная офтальмопатия, полиморфные маркеры генов.

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Aim. To analyze the association between the polymorphic markers in CTLA4, TNF, IL10 and IL16 genes and the risk of manifestation of endocrine ophthalmopathy (EO) in patients with Graves’ disease (GD).
Materials and methods. Case-control study included 248 patients with GD. Using polymerase chain reaction we studied the distribution of alleles and genotypes of polymorphic markers such as A60G (rs3087243) in CTLA4 gene, G(-308)A (rs1800629) in TNF gene, G(-1082)A (rs1800896) in IL10 gene, T3249C (rs4778641) in IL16 gene among 141 patients with Graves’ disease and EO and 107 patients with GD without EO.
Results and discussion. The frequencies of A alleles and the AA genotypes were significantly increased and the frequencies of G alleles and the GG genotype polymorphic markers rs3087243 of CTLA4 gene and rs1800896 of IL10 gene, as well as the GG genotype polymorphic marker rs1800629 of TNF gene were reduced in patients with GD and EO. The polymorphism in CTLA4 gene was also associated with the activity and the severity of EO. The comparative analysis of the allele and genotype frequency distribution of polymorphic markers of IL16 gene did not show the significant difference.
Conclusion. The risk of manifestation and the development of EO in patients with Graves’ disease can be caused by not only environmental, but also genetic risk factors.

Keywords: Graves’ disease, endocrine ophthalmopathy, polymorphic genetic markers.

Список литературы

1. Zhu W, Liu N, Zhao Y, Jia H, Cui B, Ning G. Association analysis of polymorphisms in IL-3, IL-4, IL-5, IL-9, and IL-13 with Graves’ disease. J Endocrinol Invest. 2010;33:751-755. doi: 10.1155/2014/537969
2. Niyazoglu M, Baykara O, Koc A, Aydoğdu P, Onaran I, Dellal FD, Tasan E, Sultuybek GK. Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α with Graves Disease and Graves Ophthalmopathy. Gene. 2014 Sep 1;547(2):226-232. doi: 10.1016/j.humimm.2004.02.033
3. Liu N, Li X, Liu C, Zhao Y, Cui B, Ning G. The association of interleukin-1alpha and interleukin-1beta polymorphisms with the risk of Graves’ disease in a case-control study and meta-analysis. Hum Immunol. 2010;71:39740. doi: 10.1038/eye.2009.244
4. Du P, Ma X, Wang C. Associations of CTLA4 Gene Polymorphisms with Graves’ Ophthalmopathy: A Meta-Analysis. Int J Genomics. 2014;2014:537969. doi: 10.1167/iovs.09-4965
5. Bednarczuk T, Hiromatsu Y, Seki N, Ploski R, Fukutani T, Kurylowicz A, Jazdzewski K, Chojnowski K, Itoh K, Nauman J. Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves’ ophthalmopathy. Hum Immunol. 2004;65:632-639. doi: 10.1186/1423-0127-19-97
6. Anvari M, Khalilzadeh O, Esteghamati A, Esfahani SA, Rashidi A, Etemadi A, Mahmoudi M, Amirzargar AA. Genetic susceptibility to Graves’ ophthalmopathy: the role of polymorphisms in proinflammatory cytokine genes. Eye (Lond). 2010 Jun;24(6):1058-1063. doi: 10.3109/13816810.2010.515648
7. Liu YH, Chen RH, Wu HH, Liao WL, Chen WC, Tsai Y, Tsai CH, Wan L, Tsai FJ. Association of interleukin-1 beta (IL1B) polymorphisms with Graves' ophthalmopathy in Taiwan Chinese patients. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6238-6246. doi: 10.1007/BF03346682
8. Liu YH, Chen CC, Liao LL, Wan L, Tsai CH, Tsai FJ. Association of IL12B polymorphisms with susceptibility to Graves ophthalmopathy in a Taiwan Chinese population. J Biomed Sci. 2012 Nov 19;19:97. doi: 10.1016/j.gene.2014.06.038
9. Khalilzadeh O, Anvari M, Esteghamati A, Momen-Heravi F, Rashidi A, Amiri HM, Tahvildari M, Mahmoudi M, Amirzargar A. Genetic susceptibility to Graves’ ophthalmopathy: The role of polymorphisms in anti-inflammatory cytokine genes. Ophthalmic Genet. 2010;31:215-220. doi: 10.1016/j.humimm.2010.01.023
10. Серкин Д.М., Серебрякова О.В., Серкин М.А., Харинцева С.В., Страмбовская Н.Н., Дагбаева С.Д. Роль полиморфизмов PRO12ALA и C1431T PPARγ в развитии эндокринной офтальмопатии. Клиническая и экспериментальная тиреоидология. 2013;9(3)51-55 [Serkin DM, Serebryakova OV, Serkin MA, Kharintseva SV, Strambovskaya NN, Dagbaeva SD. The role of PRO12ALA and C1431T PPARγ polymorphisms in the development of endocrine ophthalmopathy. Klinicheskaya i Eksperimental'naya Tireoidologiya. 2013;9(3):51-55 (In Russ.)]. doi: 10.14341/ ket20139351-55
11. Vaidya B, Imrie H, Perros P, Dickinson J, McCarthy M.I, Kendall-Taylor P, Pearce SH. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy. Lancet. 1999;354:743-744. doi: 10.1016/S0140-6736(99)01465-8
12. Zhang Q, Yang YM, Lv XY. Association of Graves’ disease and Graves’ ophthalmopathy with the polymorphisms in promoter and exon 1 of cytotoxic T lymphocyte associated antigen-4 gene. J Zhejiang Univ Sci B. 2006 Nov;7(11):887-891. doi: 10.1631/jzus.2006.B0887
13. Esteghamati A, Khalilzadeh O, Mobarra Z, Anvari M, Tahvildari M, Amiri HM, Rashidi A, Solgi G, Parivar K, Nikbin B, Amirzargar A. Association of CTLA-4 gene polymorphism with Graves’ disease and ophthalmopathy in Iranian patients. Eur J Intern Med. 2009 Jul;20(4):424-428. doi: 10.1631/jzus.2006.B0887
14. Han S, Zhang S, Zhang W, Li R, Li Y, Wang Z, Xie Y, Mao Y. CTLA4 polymorphisms and ophthalmopathy in Graves’ disease patients: association study and meta-analysis. Hum Immunol. 2006;67:618626. doi: 10.1016/j.humimm.2006.05.003
15. Zaletel K, Krhin B, Gaberscek S, Pirnat E, Hojker S. The influence of the exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene on thyroid antibody production in patients with newly diagnosed Graves’ disease. Thyroid. 2002;12:373-376. doi: 10.1089/105072502760043431
16. Yan SL, Wang YX. The relevance of tumor necrosis factor alpha gene-863C/A polymorphism with thyroid-associated ophthalmopathy. Zhonghua Yan Ke Za Zhi. 2005;41:786-790. doi: 10.3760/j:issn:0412-4081.2005.09.005

________________________________________________

1. Zhu W, Liu N, Zhao Y, Jia H, Cui B, Ning G. Association analysis of polymorphisms in IL-3, IL-4, IL-5, IL-9, and IL-13 with Graves’ disease. J Endocrinol Invest. 2010;33:751-755. doi: 10.1155/2014/537969
2. Niyazoglu M, Baykara O, Koc A, Aydoğdu P, Onaran I, Dellal FD, Tasan E, Sultuybek GK. Association of PARP-1, NF-κB, NF-κBIA and IL-6, IL-1β and TNF-α with Graves Disease and Graves Ophthalmopathy. Gene. 2014 Sep 1;547(2):226-232. doi: 10.1016/j.humimm.2004.02.033
3. Liu N, Li X, Liu C, Zhao Y, Cui B, Ning G. The association of interleukin-1alpha and interleukin-1beta polymorphisms with the risk of Graves’ disease in a case-control study and meta-analysis. Hum Immunol. 2010;71:39740. doi: 10.1038/eye.2009.244
4. Du P, Ma X, Wang C. Associations of CTLA4 Gene Polymorphisms with Graves’ Ophthalmopathy: A Meta-Analysis. Int J Genomics. 2014;2014:537969. doi: 10.1167/iovs.09-4965
5. Bednarczuk T, Hiromatsu Y, Seki N, Ploski R, Fukutani T, Kurylowicz A, Jazdzewski K, Chojnowski K, Itoh K, Nauman J. Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves’ ophthalmopathy. Hum Immunol. 2004;65:632-639. doi: 10.1186/1423-0127-19-97
6. Anvari M, Khalilzadeh O, Esteghamati A, Esfahani SA, Rashidi A, Etemadi A, Mahmoudi M, Amirzargar AA. Genetic susceptibility to Graves’ ophthalmopathy: the role of polymorphisms in proinflammatory cytokine genes. Eye (Lond). 2010 Jun;24(6):1058-1063. doi: 10.3109/13816810.2010.515648
7. Liu YH, Chen RH, Wu HH, Liao WL, Chen WC, Tsai Y, Tsai CH, Wan L, Tsai FJ. Association of interleukin-1 beta (IL1B) polymorphisms with Graves' ophthalmopathy in Taiwan Chinese patients. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6238-6246. doi: 10.1007/BF03346682
8. Liu YH, Chen CC, Liao LL, Wan L, Tsai CH, Tsai FJ. Association of IL12B polymorphisms with susceptibility to Graves ophthalmopathy in a Taiwan Chinese population. J Biomed Sci. 2012 Nov 19;19:97. doi: 10.1016/j.gene.2014.06.038
9. Khalilzadeh O, Anvari M, Esteghamati A, Momen-Heravi F, Rashidi A, Amiri HM, Tahvildari M, Mahmoudi M, Amirzargar A. Genetic susceptibility to Graves’ ophthalmopathy: The role of polymorphisms in anti-inflammatory cytokine genes. Ophthalmic Genet. 2010;31:215-220. doi: 10.1016/j.humimm.2010.01.023
10.[Serkin DM, Serebryakova OV, Serkin MA, Kharintseva SV, Strambovskaya NN, Dagbaeva SD. The role of PRO12ALA and C1431T PPARγ polymorphisms in the development of endocrine ophthalmopathy. Klinicheskaya i Eksperimental'naya Tireoidologiya. 2013;9(3):51-55 (In Russ.)]. doi: 10.14341/ ket20139351-55
11. Vaidya B, Imrie H, Perros P, Dickinson J, McCarthy M.I, Kendall-Taylor P, Pearce SH. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy. Lancet. 1999;354:743-744. doi: 10.1016/S0140-6736(99)01465-8
12. Zhang Q, Yang YM, Lv XY. Association of Graves’ disease and Graves’ ophthalmopathy with the polymorphisms in promoter and exon 1 of cytotoxic T lymphocyte associated antigen-4 gene. J Zhejiang Univ Sci B. 2006 Nov;7(11):887-891. doi: 10.1631/jzus.2006.B0887
13. Esteghamati A, Khalilzadeh O, Mobarra Z, Anvari M, Tahvildari M, Amiri HM, Rashidi A, Solgi G, Parivar K, Nikbin B, Amirzargar A. Association of CTLA-4 gene polymorphism with Graves’ disease and ophthalmopathy in Iranian patients. Eur J Intern Med. 2009 Jul;20(4):424-428. doi: 10.1631/jzus.2006.B0887
14. Han S, Zhang S, Zhang W, Li R, Li Y, Wang Z, Xie Y, Mao Y. CTLA4 polymorphisms and ophthalmopathy in Graves’ disease patients: association study and meta-analysis. Hum Immunol. 2006;67:618626. doi: 10.1016/j.humimm.2006.05.003
15. Zaletel K, Krhin B, Gaberscek S, Pirnat E, Hojker S. The influence of the exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene on thyroid antibody production in patients with newly diagnosed Graves’ disease. Thyroid. 2002;12:373-376. doi: 10.1089/105072502760043431
16. Yan SL, Wang YX. The relevance of tumor necrosis factor alpha gene-863C/A polymorphism with thyroid-associated ophthalmopathy. Zhonghua Yan Ke Za Zhi. 2005;41:786-790. doi: 10.3760/j:issn:0412-4081.2005.09.005

Авторы

Н.А. Петунина 1, Н.С. Мартиросян 1, Л.В. Трухина 1, С.В. Саакян 2, О.Г. Пантелеева 2,
А.М. Бурденный 3, В.В. Носиков 3

1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
2 ФГБУ «Московский научно-исследовательский институт глазных болезней им. Гельмгольца» Минздрава России, Москва, Россия;
3 ФГБУН «Институт биохимической физики им. Н.М. Эмануэля» Российской академии наук, Москва, Россия

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N.A. Petunina 1, N.S. Martirosian 1, L.V. Trukhina 1, S.V. Saakyan 2, O.G. Panteleeva 2, A.M. Burdennyy 3, V.V. Nosikov 3

1 I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), Moscow, Russia;
2 Moscow Helmholtz Research Institute of Eye Diseases, Moscow, Russia;
3 N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia

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