mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2018-2-193-202mimmun-1484Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESАНТИТЕЛА К БЕНЗО[А]ПИРЕНУ, ЭСТРАДИОЛУ И ПРОГЕСТЕРОНУ И ГЕНЕТИЧЕСКИЙ ПОЛИМОРФИЗМ ЦИТОКИНОВ: АССОЦИАЦИИ С РАКОМ ЛЕГКОГО У МУЖЧИНANTIBODIES TO BENZO[A]PYRENE, ESTRADIOL AND PROGESTERONE AND GENE POLYMORPHISMS OF CYTOKINES: ASSOCIATIONS WITH LUNG CANCER IN MENГлушковА. Н.GlushkovA. N.

д.м.н., профессор, директор

профессор кафедры генетики биологического факультета 

PhD, MD (Medicine), Professor, Director, Institute of Human Ecology

Professor, Department of Genetics, Institute of Ecology, Biodiversity and Natural Resources

ПоленокЕ. Г.PolenokE. G.

к.фарм.н., ведущий научный сотрудник лаборатории иммунохимии Института экологии человека 

650065, Россия, г. Кемерово, пр. Ленинградский, 10. Тел./факс: 8 (3842) 57-50-79

PhD (Pharmacy), Leading Research Associate, Laboratory of Immunochemistry

650065, Russian Federation, Kemerovo, Leningradsky ave, 10. Phone/Fax: 7 (3842) 57-50-79

egpolenok@mail.ruГордееваЛ. А.GordeevaL. A.

к.б.н., ведущий научный сотрудник лаборатории иммуногенетики Института экологии человека

PhD (Biology), Leading Research Associate, Laboratory of Immunogenetics, Institute of Human Ecology

МунС. А.MunS. A.

к.м.н., старший научный сотрудник лаборатории иммуногенетики Института экологии человека

PhD (Medicine), Senior Research Associate, Laboratory of Immunogenetics, Institute of Human Ecology

КостянкоМ. В.KostyankoM. V.

ведущий инженер кафедры органической химии Института фундаментальных наук

Leading Engineer, Department of Organic Chemistry, Institute of Fundamental Sciences

ТитовВ. А.TitovV. A.

заведующий торакальным отделением

Chief, Thoracic Department

ВафинИ. А.VafinI. A.

главный врач

Physician-in-Chief

РагожинаС. Е.RagozhinaS. E.

заместитель главного врача по медицинской части

Deputy Physician-in-Chief for Medicine

ФГБНУ «Федеральный исследовательский центр угля и углехимии» Сибирского отделения Российской академии наук, Институт экологии человека; ФГБОУ ВО «Кемеровский государственный университет»РоссияFederal Research Center of Coal and Coal Chemistry, Siberian Branch of the Russian Academy of Sciences, Institute of Human Ecology; Kemerovo State UniversityRussian FederationФГБНУ «Федеральный исследовательский центр угля и углехимии» Сибирского отделения Российской академии наук, Институт экологии человека;РоссияFederal Research Center of Coal and Coal Chemistry, Siberian Branch of the Russian Academy of Sciences, Institute of Human EcologyRussian FederationГБУЗ КО «Областной клинический онкологический диспансер»РоссияRegional Clinical Oncology DispensaryRussian FederationГКУЗ КО «Кемеровский областной центр крови»РоссияRegional Center of BloodRussian Federation201815032018202193202Copyright © Глушков А.Н., Поленок Е.Г., Гордеева Л.А., Мун С.А., Костянко М.В., Титов В.А., Вафин И.А., Рагожина С.Е., 20182018Глушков А.Н., Поленок Е.Г., Гордеева Л.А., Мун С.А., Костянко М.В., Титов В.А., Вафин И.А., Рагожина С.Е.Glushkov A.N., Polenok E.G., Gordeeva L.A., Mun S.A., Kostyanko M.V., Titov V.A., Vafin I.A., Ragozhina S.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1484

Ранее обнаружили ассоциации антител, специфичных к химическим канцерогенам и стероидным гормонам, с раком легкого. Однако механизмы их образования и действия остаются не вполне понятными. В частности, неизвестно, взаимосвязано ли их содержание в сыворотке крови с генетическим полиморфизмом цитокинов.

Цель исследования – выявить предполагаемые ассоциации антител класса А, специфичных к бензо[а]пирену, эстрадиолу и прогестерону (IgA-Bp, IgA-Es и IgA-Pg) в совокупности с полиморф- ными вариантами генов (IL1RN, IL1В, IL4, IL6, IL10, TNFA) с раком легкого у мужчин.

Были обследованы курящие мужчины: 381 больной раком легкого и 158 условно здоровых доноров без патологии органов дыхания. Исследование антител было выполнено с помощью твердофазного неконкурентного иммуноферментного анализа. Типирование полиморфизма генов IL1RN (VNTR, интрон 2), IL4 (VNTR, интрон 3) проводили с помощью ПЦР, генов IL1B (rs1143634) и IL6 (rs1800795) – с помощью полиморфизма длин рестрикционных фрагментов (ПДРФ), генов TNFA (rs1800629, rs361525) и IL10 (rs1800896) – с помощью TaqMan ПЦР в режиме реального времени.

У больных раком легкого доля случаев с уровнями IgA-Pg, превышающими уровни IgA-Bp и IgA-Es, была значимо меньше, чем у здоровых (OR = 0,31; p < 0,0001). И наоборот, превышение уровней и IgABp и IgA-Es над уровнями IgA-Pg встречалось чаще у больных раком легкого (OR = 3,6; p < 0,0001). Не выявлено искомых взаимосвязей уровней исследуемых антител с генетическим полиморфизмом цитокинов. Вместе с тем обнаруженные ассоциации соотношений IgA-Bp и IgA-Es с IgA-Pg проявлялись только у носителей определенных генотипов цитокинов, в частности у гетерозигот AG гена IL10.

Полученные результаты косвенно подтверждают предположение, что IgA-Bp и IgA-Es стимулируют возникновение рака легкого, воздействуя на фазы инициации и промоции. IgA-Pg ингибирует канцерогенез, воздействуя на фазу промоции. Показана высокая информативность иммуноанализа IgA-Bp и IgA-Es и IgA-Pg в сочетании с молекулярно-генетическим анализом IL10 для определения риска рака легкого у курящих мужчин.

Previous studies have revealed associations of antibodies, specific to chemical carcinogens and steroid hormones with lung cancer in men. However, the mechanisms of their formation and action were remained unclear. In particular, the relationships between antibodies and gene polymorphisms of cytokines were un- known. The purpose of this study was to identify possible associations between occurrence of A class antibodies, specific to benzo[a]pyrene, estradiol and progesterone (IgA-Bp, IgA-Es and IgA-Pg), and frequency of genetic polymorphisms of IL1RN VNTR, IL1В (rs1143634, rs16944), IL4 VNTR, IL6 (rs1800795), IL10 (rs1800896), TNFA (rs1800629, rs361525) genes in healthy male smokers and lung cancer patients.

We have examined 381 men with non-small cell lung cancer and 158 apparently healthy donors without respiratory diseases. A non-competitive solid phase immunoassay of antibodies was performed. Analysis of polymorphic loci of IL1RN (VNTR, intron 2), IL4 (VNTR, intron 3) was performed by means of conventional PCR; IL1В (rs1143634, rs16944), IL6 (rs1800795) SNPs were detected by RFLP, and IL10 (rs1800896), TNFA (rs1800629, rs361525) genotyping was carried out with TaqMan Real-time PCR. Results of the study have shown that the proportion of cases with high level of IgA-Pg and low levels of both IgA-Bp and IgA-Es among the lung cancer patients was lower than in healthy men (OR = 0.31, p < 0.0001). Vice versa, the ratio of cases with high levels of both IgA-Bp and IgA-Es and low levels of IgA-Pg was higher in lung cancer patients (OR = 3.6, p < 0.0001). No relationships were revealed between the levels of antibodies, and rates of genetic polymorphisms for the studied cytokines in both groups of men. At the same time, the detected associations of IgA-Bp, IgA-Es and IgA-Pg with lung cancer proved to be significant only in carriers of certain cytokine genotypes, e.g., in AG IL10 heterozygotes (OR = 5.1, p < 0.0001).

In conclusion, these results provide indirect evidence that IgA-Bp and IgA-Es could stimulate initiation and promotion of lung carcinogenesis. On the contrary, IgA-Pg could inhibit the promotion of carcinogenesis. Immunoassay of these antibodies combined with molecular biology studies of IL10 gene variants are recommended for the lung cancer risk assessment.

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