vestimИзвестия Национальной академии наук Беларуси. Серия медицинских наукProceedings of the National Academy of Sciences of Belarus, Medical series1814-60232524-2350The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1814-6023-2025-22-4-332-343vestim-1059Research ArticleКЛИНИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАCLINICAL AND EXPERIMENTAL MEDICINEАссоциация полиморфизмов генов MICA и CTLA-4 с риском аутоиммунных заболеваний щитовидной железы у детей с сахарным диабетом 1-го типаAssociation of MICA and CTLA-4 gene polymorphisms with the risk of autoimmune thyroid diseases in children with type 1 diabeteshttps://orcid.org/0009-0008-0189-7047ВолковаН. В.VolkovaN. V.

Волкова Наталия Васильевна – аспирант, Белорусскийгосударственный медицинский университет; врач детский эндокринолог

пр. Дзержинского, 83, 220083, г. Минск

ул. Нарочанская, 17, 220020, г. Минск

Natalya V. Volkova – Postgraduate student; pediatric endocrinologist

83, Dzerzhinski Ave., 220083, Minsk

17, Narochanskaya Str., 220020, Minsk

volkova_nv@tut.byАксёноваЕ. А.AksenovaE. A.

Аксёнова Елена Анатольевна – канд. биол. наук

ул. Академическая, 27, 220072, г. Минск

Elena A. Aksenova – Ph. D. (Biol.)

27, Akademicheskaya Str., 220072, Minsk

СолнцеваА. В.SolntsevaA. V.

Солнцева Анжелика Викторовна – д-р мед. наук, профессор, директор; 

заведующий кафедрой

пр. Дзержинского, 83, 220116, г. Минск

ул. Фрунзенская, 43, 223053, д. Боровляны, Минский р-н

Angelika V. Solntseva – D. Sc. (Med.), Professor, Director; Head of the Department

83, Dzerzhinski Ave., 220083, Minsk

43, Frunze Str., 223053, Borovlyany v., Minsk region

ang_solntseva@mail.ruЖаричВ. М.ZharichV. M.

Жарич Виктор Михайлович – науч. сотрудник

ул. Академическая, 27, 220072, г. Минск

Victor M. Zharich – Researcher

27, Akademicheskaya Str., 220072, Minsk

АлександровичВ. В.AleksandrovichV. V.

Александрович Валерия Вадимовна – мл. науч. сотрудник

ул. Академическая, 27, 220072, г. Минск

Valeria V. Aleksandrovich – Junior Researcher

27, Akademicheskaya Str., 220072, Minsk

СинявскаяМ. Г.SiniauskayaM. G.

Синявская Марина Георгиевна – канд. биол. наук, заведующий лабораторией

ул. Академическая, 27, 220072, г. Минск

Maryna G. Siniauskaya – Ph. D. (Biol.), Head of the Laboratory

27, Akademicheskaya Str., 220072, Minsk

m.sin@inbox.ruБелорусский государственный медицинский университет; 2-я городская детская клиническая больницаBelarusian State Medical University; 2nd City Children’s Clinical HospitalИнститут генетики и цитологии Национальной академии наук БеларусиInstitute of Genetics and Cytology of the National Academy of Sciences of BelarusБелорусский государственный медицинский университет; Республиканский научно-практический центр детской онкологии, гематологии и иммунологииBelarusian State Medical University; Republican Scientific and Practical Center for Pediatric Oncology, Hematology and Immunology202504122025224332343Copyright © Волкова Н.В., Аксёнова Е.А., Солнцева А.В., Жарич В.М., Александрович В.В., Синявская М.Г., 20252025Волкова Н.В., Аксёнова Е.А., Солнцева А.В., Жарич В.М., Александрович В.В., Синявская М.Г.Volkova N.V., Aksenova E.A., Solntseva A.V., Zharich V.M., Aleksandrovich V.V., Siniauskaya M.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestimed.belnauka.by/jour/article/view/1059

CTLA-4 и MICA являются общими генами-кандидатами сахарного диабета (СД) 1-го типа и аутоим- мунных тиреоидных заболеваний (АИТЗ). Результаты исследований связи полиморфных вариантов CT60 (+6230G>A) (rs3087243) гена CTLA-4 и STR в 5-м экзоне гена MICA с восприимчивостью к аутоиммунным эндокринопатиям значительно варьируются в разных странах. Представляло интерес генотипирование детей с изолированным СД  1-го типа и в сочетании с АИТЗ (аутоиммунным полигландулярным синдромом 3а типа – АПС 3а типа) для установления генетических маркеров риска тиреопатий у детей с СД 1-го типа в Беларуси.

В работе определены частоты аллелей и генотипов rs3087243 гена CTLA-4 и STR в 5-м экзоне гена MICA у детей с АПС 3а типа (n = 52), СД 1-го типа (n = 95) и в контрольной группе (n = 40).

У детей с АПС 3а типа значительно чаще регистрировали генотип GG по rs3087243 гена CTLA-4, чем у пациентов с СД 1-го типа (GG vs AA/AG: ОШ = 5,06 (1,12–22,97)) и в группе контроля (GG vs AA/AG: ОШ = 5,30 (1,04–27,12)). Установлено, что генотип А5.1/5.1 по STR в 5-м экзоне гена MICA связан с повышенной вероятностью сочетанного развития СД 1-го типа и АИТЗ (ОШ = 3,65 (1,10‒12,05), Fдв = 0,05, р = 0,037). Выявлена ассоциация аллеля MICA-А9 с предрасположенностью к АПС 3а типа у девочек с СД 1-го типа (ОШ = 2,60 (1,17‒5,74)), в особенности сопровождающегося наиболее тяжелыми формами тиреоидной патологии: манифестным гипотиреозом (ОШ = 6,42 (1,70‒24,24)) и гипертрофией щитовидной железы (ОШ = 7,78 (1,81‒33,38)).

Полученные данные позволяют выделить генотип GG по rs3087243 гена CTLA-4 как фактор риска АПС 3а типа у детей с СД 1-го типа; носительство аллеля MICA-А9 – как фактор риска АИТЗ с манифестным гипотиреозом и зобом у девочек с СД 1-го типа.

CTLA-4 and MICA are common candidate genes for type 1 diabetes (T1D) and autoimmune thyroid diseases (AITD). The data concerning the association of CT60 (+6230G>A) (rs3087243) polymorphism within the CTLA-4 gene and the short tandem repeats (STR) in exon 5 of the MICA gene with autoimmune endocrinopathies are distinct in different populations. This work was aimed to reveal the alleles and genotypes associated with a predisposition to AITD in children with T1D in Belarus.

We investigated the allele and genotype frequencies of CTLA-4 rs3087243 and the STR in exon 5 of MICA in children diagnosed with autoimmune polyglandular syndrome (APS) type 3a (n = 52), T1D (n = 95) and control group (n = 40).

A comparative analysis of the genotype distribution of CTLA-4 rs3087243 polymorphism showed that children with APS type 3a were significantly more likely to have the GG genotype compared with patients with T1D (OR = 5.06 (1.12–22.97)) and the control group (OR = 5.30 (1.04–27.12)). It was found that MICA-A5.1/5.1 genotype is associated with an increased risk of the combined development of T1D and AITD (OR = 3.65 (1.10‒12.05)). We revealed the association of the MICA-A9 allele with a predisposition to APS type 3a in girls with T1D (OR = 2.60 (1.17‒5.74)), especially with the most severe thyroid pathology: overt hypothyroidism (OR = 6.42 (1.70‒24.24)) and thyroid hypertrophy (OR = 7.78 (1.81‒33.38)).

The obtained data identify the GG genotype at rs3087243 (CTLA-4) as a risk factor for APS type 3a in children  with T1D; and the MICA-A9 allele – for AITD with overt hypothyroidism and goiter in girls with T1D.

сахарный диабет 1-го типааутоиммунный полигландулярный синдром 3а типагенетический полиморфизмдетиMICACTLA-4type 1 diabetes mellitusautoimmune polyglandular syndrome type 3agenetic polymorphismchildrenMICACTLA-4Работа выполнена по договору № 2018-28-006 от 23.03.2018 на выполнение НИОК(Т)Р вне рамок государственных программ, государственных (отраслевых) научно-технических программ за счет средств республиканского централизованного инновационного фонда. Авторы выражают благодарность сотрудникам лабораторий нехромосомной наследственности и молекулярных основ стабильности генома Института генетики и цитологии Национальной академии наук Беларуси, принявшим участие в исследовании.The work was performed under contract No. 2018-28-006 dated 03.23.2018 for the performance of researches outside the state programs, state (sectoral) scientific and technical programs at the expense of the republican centralized innovation fund. 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The authors declare that there are no conflicts of interest present.