Perm Medical JournalPerm Medical JournalПермский медицинский журнал (сетевое издание "Perm medical journal")0136-14492687-1408Eco-Vector10426610.17816/pmj39147-65Original studiesОригинальные исследованияResearch ArticleGenetic regulation of cytokine inflammation in oncohematological diseasesГенетическая регуляция цитокинового воспаления при онкогематологических заболеванияхhttps://orcid.org/0000-0002-3043-8674LoshkovaE. V.ЛошковаЕ. В.
Russian Federation

Candidate of Medical Sciences, senior researcher of Department of Congenital and Metabolic Diseases

кандидат медицинских наук, старший научный сотрудник отдела наследственных и метаболических заболеваний

loshkova@rambler.ruhttps://orcid.org/0000-0002-9326-4085PonomarenkoYu. B.ПономаренкоЮ. Б.
Russian Federation

pediatrician

врач-педиатр

loshkova@rambler.ruKondratievaE. I.КондратьеваЕ. И.
Russian Federation

MD, PhD, Professor, Head of the Scientific and Clinical Department of Cystic Fibrosis

доктор медицинских наук, профессор, руководитель научно-клинического отдела муковисцидоза

loshkova@rambler.ruLebedevV. V.ЛебедевВ. В.
Russian Federation

Head of Unit of Oncology and Hematology with Chemotherapy

заведующий отделением онкологии и гематологии с химиотерапией

loshkova@rambler.ruhttps://orcid.org/0000-0003-0322-4715KleschenkoE. I.КлещенкоЕ. И.
Russian Federation

Chief Physician, Head of Department of Pediatrics with Course of Neonatology

главный врач, заведующая кафедрой педиатрии с курсом неонатологии ФПК и ППС

loshkova@rambler.ruScientific Research Clinical Institute of Childhood of the Ministry of Health of the Moscow RegionНаучно-исследовательский клинический институт детства Министерства здравоохранения Московской областиChildren's Regional Clinical HospitalДетская краевая клиническая больницаKuban State Medical UniversityКубанский государственный медицинский университет1501202239147650103202201032022Copyright ©; 2022, Loshkova E.V., Ponomarenko Y.B., Kondratieva E.I., Lebedev V.V., Kleschenko E.I.Copyright ©; 2022, Лошкова Е.В., Пономаренко Ю.Б., Кондратьева Е.И., Лебедев В.В., Клещенко Е.И.2022Loshkova E.V., Ponomarenko Y.B., Kondratieva E.I., Lebedev V.V., Kleschenko E.I.Лошкова Е.В., Пономаренко Ю.Б., Кондратьева Е.И., Лебедев В.В., Клещенко Е.И.http://creativecommons.org/licenses/by-sa/4.0https://permmedjournal.ru/PMJ/article/view/104266

Objective. To analyze the correlations of the polymorphous variants of the genes – the modifiers of immune response (IL1-β/+3953, IL1RN*VNTR, TNFA*G-308A) with the development of oncohematological diseases (OHD) and the production of pro-and anti-inflammatory cytokines (IL-1β, IL-1Ra, TNF-α, INF-γ, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18).

Materials and methods. The examination included 100 children (57 (57 %) boys и 43 (43 %) girls, with the mean age 7.50 (2.5–12.60 years) suffering from malignant blood diseases. The cytokine content (IL-1β, IL-4, IL-6, IL-8, IL-18, IL-1Ra и IL-10) was determined using IFA, the genetic typing of the genetic variants of the genes of cytokines IL1-β/+3953, IL1RN*VNTR, TNFA*G-308A – PCR and RFLP methods.

Results. In case of lethal outcome, 14% of cases, the TNF-α IL-6, IL-8, IL-18 INF-γ and IL-10 levels were reliably higher, compared with the survived patients. Renal function disorder detected among 13% of children was accompanied by an increase in IL-1β, IL-6, IL-8, IL-18, IL-1Ra and INF-γ compared to the patients without nephropathy and the control group (p<0.05). Eighteen OHD children with high concentration of IL-1β, IL-1Ra, IL-6, IL-8, IL-18 and INF-γ had fractures (р<0,05). Against the background of OHD, the carriage of the genotype А2А2 of the polymorphic variant VNTR IL1RN gene was observed 13 times more often, the carriage of the allele A2 – 2.16 times more often. The carriers of the genotype A2A2 of the genetic variant VNTR IL1RN gene had an increased risk of nephropathy by 20.89 times, the carriers of the allele A2 – 3.05 times more often. Children with OHD complicated by bacterial infection by 10.77 times more often had the genotype A2A2 and by 2.45 times more often – the allele A2 of the genetic variant VNTR IL1RN gene.

Conclusions. The carriers of the minor genotype A2A2 of the gene IL1RN*VNTR had a reliably higher production of the antiinflammatory IL-1β, IL-6, IL-8, IL-18 и IL-1Ra. The carriers of the genotype GA of the gene TNFA*G-308A had a significantly higher values of IL-1β, IL-18, IL-6, IL-8, TNF-α.

Цель. Провести анализ взаимосвязей полиморфных вариантов генов – модификаторов иммунного ответа (IL1-β/+3953, IL1RN*VNTR, TNFA*G-308A) с развитием онкогематологических заболеваний и продукцией про- и противовоспалительных цитокинов (IL-1β, IL-1Ra, TNF-α, INF-γ, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18).

Материалы и методы. Обследовано 100 детей (57 (57 %) мальчиков и 43 (43 %) девочки), Ме возраста 7,50 (2,5–12,60) г.) со злокачественными заболеваниями крови. Определено содержание цитокинов (IL-1b, IL-4, IL-6, IL-8, IL-18, IL-1Ra и IL-10) методом ИФА, генотипирование генетических вариантов генов цитокинов IL1-β/+3953, IL1RN*VNTR, TNFA*G-308A методом ПЦР и ПДРФ анализа.

Результаты. При летальном исходе (14 % случаев) уровень TNF-α, IL-6, IL-8, IL-18 INF-γ и IL-10 оказался достоверно выше по сравнению с выжившими пациентами. Нарушение функции почек, выявленное у 13 % детей, сопровождалось увеличением IL-1β, IL-6, IL-8, IL-18, IL-1Ra и INF-γ по сравнению с пациентами без нефропатии и контрольной группой (р < 0,05). Переломы при онкогематологических заболеваниях отмечены у 18 детей, имевших высокую концентрацию IL-1β, IL-1Ra, IL-6, IL-8, IL-18 и INF-γ (р < 0,05). На фоне ОГЗ носительство генотипа А2А2 полиморфного варианта VNTR гена IL1RN наблюдалось в 13 раз чаще, носительство аллеля А2 в 2,16 раза чаще. Носители генотипа А2А2 генетического варианта VNTR гена IL1RN имели повышение риска нефропатии в 20,89 раза, носители аллеля А2 – в 3,05 раза. Дети с онкогематологическими заболеваниями, осложненными бактериальной инфекцией, в 10,77 раза чаще имели генотип А2А2 и в 2,45 раза – аллель А2 генетического варианта VNTR гена IL1RN.

Выводы. Носители минорного генотипа А2А2 гена IL1RN*VNTR имели достоверно более высокую продукцию провоспалительного IL-1β, IL-6, IL-8, IL-18 и IL-1Ra. Носители генотипа GA гена TNFA*G-308A имели достоверно более высокие значения IL-1β, IL-18, IL-6, IL-8, TNF-α.

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