rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2016-21-30rsp-2165Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHИсследование полиморфизмов генов-кандидатов иммунного ответа как маркеров риска развития ревматоидного артрита и продукции аутоантителINVESTIGATION OF CANDIDATE GENE POLYMORPHISMS IN AN IMMUNE RESPONSE AS MARKERS FOR THE RISK OF DEVELOPING RHEUMATOID ARTHRITIS AND PRODUCING AUTOANTIBODIESГусеваИ. А.GusevaI. A.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

irrgus@yandex.ruДемидоваН. В.DemidovaN. V.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

СорокаН. Е.SorokaN. E.

109383 Москва, ул. Гурьянова, 83, корп. 1

83, Guryanov St., Build. 1, Moscow 109383

ЛучихинаЕ. Л.LuchikhinaE. L.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

НовиковА. А.NovikovA. A.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

АлександроваЕ. Н.AleksandrovaE. N.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ЛукинаГ. В.LukinaG. V.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ФедоренкоЕ. В.FedorenkoE. V.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

АроноваЕ. С.AronovaE. S.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

СамаркинаЕ. Ю.SamarkinaE. Yu.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

ТрофимовД. Ю.TrofimovD. Yu.

109383 Москва, ул. Гурьянова, 83, корп. 1

83, Guryanov St., Build. 1, Moscow 109383

КаратеевД. Е.KarateevD. E.

115522 Москва, Каширское шоссе, 34А

34A, Kashirskoe Shosse, Moscow 115522

НасоновЕ. Л.NasonovE. L.

115522 Москва, Каширское шоссе, 34А;

119991 Москва, ул. Трубецкая, 8, стр. 2

34A, Kashirskoe Shosse, Moscow 115522;

8, Trubetskaya St., Build. 2, Moscow 119991

ФГБНУ Научно-исследовательский институт ревматологии им. В.А. НасоновойРоссияV.A. Nasonova Research Institute of RheumatologyRussian FederationЗАО «Научно-производственная фирма ДНК-Технология»РоссияZAO «DNA Technology Researchand-Production Firm»Russian FederationФГБНУ Научно-исследовательский институт ревматологии им. В.А. Насоновой; ГБОУ ВПО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава РоссииРоссияV.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University, Ministry of Health of RussiaRussian Federation2016220320165412130Copyright © Гусева И.А., Демидова Н.В., Сорока Н.Е., Лучихина Е.Л., Новиков А.А., Александрова Е.Н., Лукина Г.В., Федоренко Е.В., Аронова Е.С., Самаркина Е.Ю., Трофимов Д.Ю., Каратеев Д.Е., Насонов Е.Л., 20162016Гусева И.А., Демидова Н.В., Сорока Н.Е., Лучихина Е.Л., Новиков А.А., Александрова Е.Н., Лукина Г.В., Федоренко Е.В., Аронова Е.С., Самаркина Е.Ю., Трофимов Д.Ю., Каратеев Д.Е., Насонов Е.Л.Guseva I.A., Demidova N.V., Soroka N.E., Luchikhina E.L., Novikov A.A., Aleksandrova E.N., Lukina G.V., Fedorenko E.V., Aronova E.S., Samarkina E.Y., Trofimov D.Y., Karateev D.E., Nasonov E.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/2165

Цель исследования – изучить распределение генотипов и аллелей генов PTPN22, TNFAIP3, CTLA4, TNFA, IL6, IL6R, IL10, MCP1, ICAM1 у больных ревматоидным артритом (РА) и в контрольной группе здоровых лиц и оценить их значимость в качестве молекулярно-генетических маркеров предрасположенности к развитию РА. Проанализировать корреляцию включенных в исследование полиморфизмов генов с продукцией антител к циклическому цитруллинированному пептиду (АЦЦП) и IgM ревматоидного фактора (РФ).

Материал и методы

Материал и методы. Исследование проведено в рамках программы «Ранний артрит: диагностика, исход, критерии, активное лечение (РАДИКАЛ)». В проспективное наблюдение включены 122 пациента с достоверным диагнозом РА согласно критериям Американской коллегии ревматологов (АСR) 1987 г., с длительностью заболевания ≤2 лет, причем 73 (59,8%) пациента взяты под наблюдение в первые 6 мес после появления признаков заболевания. Позитивность по АЦЦП и IgM РФ выявлена у 74 (60,7%) и 81 (66,5%) пациентов соответственно. Контролем служили 314 здоровых доноров крови. Методом полимеразной цепной реакции в режиме реального времени у больных и лиц контрольной группы изучено распределение полиморфных вариантов генов PTPN22 (+1858 C >T, rs2476601), TNFAIP3 (rs675520, rs6920220, rs10499194), CTLA4 (+49A>G, rs231775 ), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -1082 A>G, rs1800896), MCP1/CCL2 (+2518A>G, rs1024611), ICAM1 (721G>A, rs1799969).

Результаты и обсуждение

Результаты и обсуждение. Проведенный анализ выявил ассоциативную связь полиморфизмов генов PTPN22 (+1858 C >T, rs2476601) и TNFAIP3 (rs675520, rs10499194) с риском развития РА: отношение шансов (ОШ) 1,5; 95% доверительный интервал (ДИ) 1,0–2,3, р=0,05; ОШ=1,5 (95% ДИ 1,1–2,0), p=0,02; ОШ=0,5 (95% ДИ 0,4–0,8), p=0,01, соответственно. Кроме того, была выявлена тенденция к положительной ассоциативной связи полиморфизма rs6920220 гена TNFAIP3 и полиморфизма rs8192284 гена IL6R с предрасположенностью к развитию РА (р=0,056). Полиморфизмы генов IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), ICAM1 (rs1799969) не были ассоциированы с риском развития РА. Анализ данных после стратификации больных по АЦЦП- и РФ-статусу (бинарная переменная) показал, что ни один из изученных полиморфизмов не был ассоциирован со статусом по РФ. В то же время для полиморфизмов rs2476601 гена PTPN22, rs675520 гена TNFAIP3, rs10499194 гена TNFAIP3 и rs1800629 гена TNFА была выявлена статистически достоверная ассоциативная взаимосвязь со статусом по АЦЦП (бинарная переменная). Уровень АЦЦП как количественная переменная был статистически значимо ассоциирован с полиморфизмами генов CTLA4 (rs231775), TNFА (rs1800629) в дозозависимой манере (р=0,025 и р=0,015 соответственно). Была выявлена выраженная тенденция к взаимосвязи уровня АЦЦП и полиморфизма гена IL6R (р=0,07). Полиморфизмы генов IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), ICAM1 (rs1799969) не коррелировали со статусом по АЦЦП (бинарная и количественная переменные).

Заключение

Заключение. Результаты проведенного исследования свидетельствуют о вкладе ряда генов в патогенез РА в целом как нозологической единицы, а также об их участии в развитии двух субтипов РА: АЦЦП-позитивного и АЦЦП-негативного. Взаимосвязь продукции IgM РФ с полиморфизмами изученных генов не была выявлена. Полученные данные свидетельствуют, по-видимому, о различных механизмах образования аутоантител (АЦЦП и IgM РФ) при РА.

Objective

Objective: to investigate the distribution of the genotypes and alleles of the PTPN22, TNFAIP3, CTLA4, TNFA, IL6, IL6R, IL10, MCP1, and ICAM1 genes in patients with rheumatoid arthritis (RA) and in the control group of healthy individuals, to estimate their significance as molecular genetic markers for predisposition to RA; and to analyze the correlation between the gene polymorphisms included in the study and the production of anti-cyclic citrullinated peptide antibodies (ACCPA) and IgM rheumatoid factor (RF).

Subjects and methods

Subjects and methods. The investigation was conducted within the framework of the «Early arthritis: Diagnosis, outcome, criteria, active treatment program». The prospective follow-up study included 122 patients with RA fulfilling the 1987 American College of Rheumatology (ACR) criteria; with disease duration of ≤ 2 years. 73 (59.8%) patients were included during the first 6 months after the onset of the disease. 74 (60.7%) and 81 (66.5%) patients were found to be positive for ACCPA and IgM RF, respectively. 314 healthy blood donors served as a control group. A real-time polymerase chain reaction was used in the patients and control individuals to study the distribution of the polymorphic variants of PTPN22 (+1858 C >T, rs2476601), TNFAIP3 (rs675520, rs6920220, rs10499194), CTLA4 (+49A>G, rs231775 ), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -1082 A>G, rs1800896), MCP1/CCL2 (+2518A>G, rs1024611), and ICAM1 (721G>A, rs1799969) genes. Results and discussion. This analysis revealed an association of PTPN22 (+1858 C >T, rs2476601) and TNFAIP3 (rs675520, rs10499194) polymorphisms with the risk of RA (odds ratio (OR), 1.5; 95% confidence interval (CI), 1.0–2.3; p = 0.05; OR, 1.5; 95% CI, 1.1–2.0; p = 0.02; OR, 0.5; 95% CI, 0.4–0.8; p = 0.01, respectively. Further, there was a tendency towards a positive association of TNFAIP3 (rs6920220) and IL6R (rs8192284) polymorphisms with a predisposition to RA (p = 0.056). IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), and ICAM1 (rs1799969) polymorphisms were not associated with the risk of RA. An analysis of the findings after patient stratification by ACCPA and IgM RF (a binary variable) showed that none of the polymorphisms in question was associated with RF state. At the same time, PTPN22 (rs2476601), TNFAIP3 (rs675520), TNFAIP3 (rs10499194), and TNFА (rs1800629) polymorphisms were found to be significantly related to ACCPA state (a binary variable). The level of ACCPA as a quantitative variable was statistically significantly associated with CTLA4 (rs231775) and TNFА (rs1800629) polymorphisms in a dose-dependent fashion (р = 0.025 and р = 0.015, respectively). There was a marked tendency towards an association of ACCPA levels and IL6R gene polymorphism (p = 0.07). IL6 (rs1800795), IL10 (rs1800872, rs1800896), MCP1/CCL2 (rs1024611), and ICAM1 (rs1799969) polymorphisms were not correlated with ACCPA state (binary and quantitative variables).

Conclusion

Conclusion. The findings suggest that a number of genes are implicated in the pathogenesis of RA and that they are involved in the development of ACCPA-positive and ACCPA-negative RA subtypes. No relationship was found between the production of IgM RF and the polymorphisms of the genes under study. The findings suggest that there appears to be different mechanisms for the formation of autoantibodies (ACCPA and IgM RF) in RA.

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