diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM13101diaendo-13101Research ArticleОригинальные исследованияOriginal StudiesАллельные варианты генов главного комплекса гистосовместимости у детей с сахарным диабетом 1 типа, заболевших в дошкольном возрастеAllelic variants of genes of the main histocompatibility complex in children with type 1 diabetes mellitus who became ill at preschool agehttps://orcid.org/0000-0002-4316-8546ЛаптевД. Н.LaptevD. N.

Лаптев Дмитрий Никитич - д.м.н.; ResearcherID: O-1826-2013; Scopus Author ID: 24341083800.

Москва

Dmitry N. Laptev - PhD; ResearcherID: O-1826-2013; Scopus Author ID: 24341083800.

Moscow

laptevdn@ya.ruhttps://orcid.org/0000-0001-7021-1151ЕреминаИ. А.EreminaI. A.

Еремина Ирина Александровна - к.м.н.; ResearcherID: S-3979-2016; Scopus Author ID: 6701334405.

Москва

Irina A. Eremina – PhD; ResearcherID: S-3979-2016; Scopus Author ID: 6701334405.

Moscow

ieremina58@gmail.comhttps://orcid.org/0000-0003-4383-7428ШубинаЕ. С.ShubinaE. S.

Шубина Екатерина Сергеевна - к.б.н.; Scopus Author ID: 57817222400.

Москва

Jekaterina S. Shubina - PhD in Biology; Scopus Author ID: 57817222400.

Moscow

e_shubina@oparina4.ruhttps://orcid.org/0000-0002-0603-3394ЯнкевичТ. Э.YankevichT. E.

Янкевич Татьяна Эдуардовна - к.м.н.; ResearcherID: 57221439561.

Москва

Tatjana E. Yankevich - PhD; ResearcherID: 57221439561.

Moscow

tat-shapovalov@yandex.ruhttps://orcid.org/0000-0002-8181-5572СечкоЕ. А.SechkoE. A.

Сечко Елена Александровна - к.м.н.; ResearcherID: S-4114-2016; Scopus Author ID: 55880018700.

Москва

Elena A. Sechko - PhD; ResearcherID: S-4114-2016; Scopus Author ID: 55880018700.

Moscow

elena.sechko@bk.ruhttps://orcid.org/0009-0001-9765-868XГончароваН. А.GoncharovaN. A.

Гончарова Наталья Андреевна - Врач детский эндокринолог, аспирант Института детской эндокринологии ГНЦ РФ ФГБУ «НМИЦ эндокринологии» МЗ РФ , аспирант Института детской эндокринологии ГНЦ РФ ФГБУ «НМИЦ эндокринологии» МЗ РФ.

117036, Москва, ул. Дм. Ульянова, д. 11

Natalia A. Goncharova

11 Dm. Ulyanova street, 117036 Moscow

nata.goncharova.9595@mail.ruhttps://orcid.org/0000-0002-5507-4627ПетерковаВ. А.PeterkovaV. A.

Петеркова Валентина Александровна - д.м.н., профессор, академик РАН.

Москва

Valentina A. Peterkova - PhD, Professor, Academician of Russian Academy of Medical Sciences

Moscow

peterkovava@hotmail.comГНЦ РФ ФГБУ «Национальный медицинский исследовательский центр эндокринологии»РоссияEndocrinology Research CentreRussian FederationНациональный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. В.И. КулаковаРоссияNational Medical Research Center For Obstetrics, Gynecology And Perinatology Named After Academician V.I.KulakovRussian FederationООО «НПФ ДНК-Технология»РоссияNPF DNA Technology LLCRussian Federation202403092024274313320Copyright © Лаптев Д.Н., Еремина И.А., Шубина Е.С., Янкевич Т.Э., Сечко Е.А., Гончарова Н.А., Петеркова В.А., 20242024Лаптев Д.Н., Еремина И.А., Шубина Е.С., Янкевич Т.Э., Сечко Е.А., Гончарова Н.А., Петеркова В.А.Laptev D.N., Eremina I.A., Shubina E.S., Yankevich T.E., Sechko E.A., Goncharova N.A., Peterkova V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/13101ОБОСНОВАНИЕ

ОБОСНОВАНИЕ. Сахарный диабет 1 типа (СД1) — хроническое аутоиммунное заболевание, характеризующееся поражением инсулинопродуцирующих клеток поджелудочной железы, что со временем приводит к потребности в заместительной инсулинотерапии. Клиническая картина СД1 гетерогенна: начало заболевания в раннем возрасте характеризуется более острой манифестацией и быстрым истощением остаточной секреции инсулина. Вариации HLA-генов, вероятно, могут определять клинические особенности течения СД1. Установлены возрастные особенности HLA-генов в различных популяциях, однако для российской популяции такие данные отсутствуют.

ЦЕЛЬ

ЦЕЛЬ. Изучить влияние HLA-генов на предрасположенность к СД1 в дошкольном возрасте.

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ И МЕТОДЫ. Одноцентровое одномоментное исследование, включающее 885 детей (1–18 лет) с СД1, находящихся на интенсифицированной инсулинотерапии. Участники разделены на две группы: с манифестацией СД1 <7 лет и ≥7 лет. Проанализированы возраст диагностики СД1, SDS индекса массы тела, уровни гликированного гемоглобина (HbA1c) и С-пептида, частота выявления аутоантител к глутаматдекарбоксилазе (GADA), тирозинфостфазе (IA-2А), транспортеру цинка (ZnT8A), генов HLA I и II классов.

РЕЗУЛЬТАТЫ

РЕЗУЛЬТАТЫ. В группе с манифестацией СД1 <7 лет выявлены более низкие показатели С-пептида (0 против 0,3 нг/мл, р<0,001), реже определялись АТ GADA (48% против 67%, р=0,028), IA-2 (52% против 62%, р=0,014), ZnT8 (44% против 71%, р=0,002). Не было значимых различий по полу, уровню HbA1c и SDS ИМТ. В группе с ­манифестацией СД1<7 лет отмечалась большая частота наиболее сильного предрасполагающего генотипа DRB1*03-DQA1*05:01-DQB1*02:01 (DR3-DQ2)/DRB1*04-DQA1*03:01-DQB1*03:02 (DR4-DQ8) (27,5% против 21,5%, p=0,039]) и меньшая частота протекторного гаплотипа DRB1*01-DQA1*01-DQB1*05:01 (19,1% против 24,9%, р=0,035). В группе с манифестацией <7 лет была большая частота предрасполагающего гаплотипа A*24:02 (35,6% против 24,1%, р=0,002). Независимо от возраста начала и длительности заболевания, отсутствие остаточной секреции С-пептида (<0,1нг/мл) было связано с предрасполагающим гаплотипом DR4-DQ8 (65,7% ­против 60,8%, р=0,04) и B*18:01 (20,9% против 16,9%, р=0,026), с меньшей частотой протекторных гаплотипов DRB1*15-DQA1*01:03-DQB1*06:03 или DRB1*15-DQA1*01:02-DQB1*06:02 (1,3% против 3,3%, р=0,047). Наличие IA-2А и ZnT8А было ассоциировано с гаплотипом DR4-DQ8 (28,2% против 16,5%, р=0,037, и 33,3% против 15,4%, р=0,018). GADА связаны с предрасполагающим гаплотипом DR3-DQ2 (55,0% против 34,5%, р=0,03).

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. В российской популяции установлены предрасполагающие и протекторные HLA гаплотипы I и II класса, связанные с манифестацией СД1 в дошкольном возрасте и резервной функцией бета-клеток. Показана взаимосвязь наличия островковых АТ с предрасполагающими DR3/DR4 гаплотипами, что может определять различные механизмы формирования и течения аутоиммунного процесса.

BACKGROUND

BACKGROUND: Type 1 diabetes mellitus (DM1) is a chronic autoimmune disease characterized by damage to insulin–producing cells of the pancreas, which eventually leads to the need for insulin replacement therapy. The clinical picture of DM1 is heterogeneous: the onset of the disease at an early age is characterized by a more acute manifestation and rapid depletion of residual insulin secretion. Variations of HLA genes can probably determine the clinical features of the course of DM1. To date, age-related features of HLA genes have been established in various populations, at the same time, such data are not available in the Russian population.

AIM

AIM: To study the effect of HLA genes on predisposition to DM1 in preschool age.

MATERIALS AND METHODS

MATERIALS AND METHODS: A single-center, one-stage study, including data from 885 children (1 year — 18 years old) with previously diagnosed DM1 who are on intensified insulin therapy. The study participants’re divided into two groups: a group with a manifestation of DM1 <7 years and a group with a manifestation of DM1 ≥7 years. The age of diagnosis of DM1, SDS body mass index, glycated hemoglobin (HbA1c) and C-peptide levels, specific islet autoantibodies glutamate decarboxylase (GADA), tyrosine phosphase (IA-2A), zinc transporter (ZnT8A), HLA genes of classes I and II (NGS genotyping by high-performance sequencing) were analyzed.

RESULTS

RESULTS: In the group with manifestations of DM1 <7 years, lower levels of C-peptide’re detected (0 vs. 0.3 ng/ml, p<0.001), AT GAD was less often determined (48% vs. 67%, p=0.028), IA-2 (52% vs. 62%, p=0.014), ZnT8 (44% vs. 71%, p=0.002). There were no significant differences in the sex ratio, the level of HbA1c and SDS BMI. In the group with manifestations of DM1 <7 years, there was a high frequency of the most severe predisposing genotype DRB1*03-DQA1*05:01-DQB1*02:01 (DR3-DQ2)/DRB1*04-DQA1*03:01-DQB1*03:02 (DR4-DQ8) (27.5% vs 21.5%, p=0.039]) and a lower frequency of the protective haplotype DRB1*01-DQA1*01-DQB1*05:01 (19.1% vs. 24.9%, p=0.035). With respect to class I HLA genes, in the group with manifestation <7 years, there was a high frequency of predisposing haplotype A*24:02 (35.6% vs. 24.1%, p=0.002). Regardless of the age of onset and duration of the disease, the absence of residual C-peptide secretion (<0.1ng/ml) was associated with the presence of the predisposing haplotype DR4-DQ8 (65.7% vs. 60.8%, p=0.04) and B*18:01 (20.9% vs. 16.9%, p=0.026), and also with a lower frequency of tread haplotypes DRB1*15-DQA1*01:03-DQB1*06:03 or DRB1*15-DQA1*01:02-DQB1*06:02 (1.3% vs. 3.3%, p=0.047). The presence of IA-2A and ZnT8A was associated with the DR4-DQ8 haplotype (28.2% vs. 16.5%, p=0.037, and 33.3% vs. 15.4%, p=0.018, respectively). GADAs were associated with the predisposing haplotype DR3-DQ2 (55.0% vs. 34.5%, p=0.03).

CONCLUSION

CONCLUSION: Predisposing and protective HLA haplotypes of class I and II associated with the manifestation of DM1 in preschool age and the reserve function of beta cells have been established in the Russian population. The relationship of the presence of islet AT with predisposing DR3/DR4 haplotypes is shown, which can determine various mechanisms of formation and course of the autoimmune process.

сахарный диабет 1 типаглавный комплекс гистосовместимостиаутоантителаподросткидети дошкольного возрастаtype 1 diabetes mellitusHLAautoantibodiesadolescentspreschool childrenИсследование выполнено в рамках исполнения государственного задания № 123021000040-9ReferencesRomanenkova EM, Zufarova IM, Sorokin DY, et al. Islet autoantibodies and residual beta-cell function in children with type 1 diabetes depending on age of manifestation. Diabetes Mellit. 2023;26(3):204-212. doi: https://doi.org/10.14341/DM12955Romanenkova E.M. et al. Islet autoantibodies and residual beta-cell function in children with type 1 diabetes depending on age of manifestation // Diabetes Mellit. 2023. Vol. 26, № 3. P. 204–212.ElSayed NA, Aleppo G, Aroda VR, et al. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes—2023. Diabetes Care. 2023;46(Supplement_1):S19-S40. doi: https://doi.org/10.2337/dc23-S002ElSayed N.A. et al. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes—2023 // Diabetes Care. 2023. Vol. 46, № Supplement_1. P. S19–S40.Carré A, Richardson SJ, Larger E, Mallone R. Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset? Diabetologia. 2021;64(1):15-25. doi: https://doi.org/10.1007/s00125-020-05298-yCarré A. et al. Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset? // Diabetologia. 2021. Vol. 64, № 1. P. 15–25.Battaglia M, Ahmed S, Anderson MS, et al. Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes. Diabetes Care. 2020;43(1):5-12. doi: https://doi.org/10.2337/dc19-0880Battaglia M. et al. Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes // Diabetes Care. 2020. Vol. 43, № 1. P. 5–12.Noble JA, Erlich HA. Genetics of Type 1 Diabetes. Cold Spring Harb Perspect Med. 2012;2(1):a007732-a007732. doi: https://doi.org/10.1101/cshperspect.a007732Noble J.A., Erlich H.A. Genetics of Type 1 Diabetes // Cold Spring Harb. Perspect. Med. 2012. Vol. 2, № 1. P. a007732–a007732.Inshaw JRJ, Cutler AJ, Crouch DJM, Wicker LS, Todd JA. Genetic variants predisposing most strongly to type 1 diabetes diagnosed under age 7 years lie near candidate genes that function in the immune system and in pancreatic B-cells. Diabetes Care. 2020. doi: https://doi.org/10.2337/dc19-0803Inshaw J.R.J. et al. Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells // Diabetes Care. 2020. Vol. 43, № 1. P. 169–177.Ren W, Yang D, Jiang Z, et al. Adult‐onset type 1 diabetic patients with less severe clinical manifestation have less risk DR‐DQ genotypes than childhood‐onset patients. Diabetes Metab Res Rev. 2021;37(1). doi: https://doi.org/10.1002/dmrr.3357Ren W. et al. Adult-onset type 1 diabetic patients with less severe clinical manifestation have less risk DR-DQ genotypes than childhood-onset patients // Diabetes Metab. Res. Rev. 2021. Vol. 37, № 1. P. e3357.Redondo MJ, Geyer S, Steck AK, et al. A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk. Diabetes Care. 2018;41(9):1887-1894. doi: https://doi.org/10.2337/dc18-0087Redondo M.J. et al. A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk // Diabetes Care. 2018. Vol. 41, № 9. P. 1887–1894.Seabold S, Perktold J. Statsmodels: Econometric and Statistical Modeling with Python. In: Proceedings of the 9th Python in Science Conference. ; 2010:92-96. doi: https://doi.org/10.25080/Majora-92bf1922-011Seabold S., Perktold J. Statsmodels: Econometric and Statistical Modeling with Python. Austin, Texas, 2010. P. 92–96.Sharp SA, Rich SS, Wood AR, et al. Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis. Diabetes Care. 2019;42(2):200-207. doi: https://doi.org/10.2337/dc18-1785Sharp S.A. et al. Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis // Diabetes Care. 2019. Vol. 42, № 2. P. 200–207.Noble JA, Valdes AM, Varney MD, et al. HLA Class I and Genetic Susceptibility to Type 1 Diabetes. Diabetes. 2010;59(11):2972-2979. doi: https://doi.org/10.2337/db10-0699Noble J.A. et al. HLA Class I and Genetic Susceptibility to Type 1 Diabetes // Diabetes. 2010. Vol. 59, № 11. P. 2972–2979.Zhang J, Zhao L, Wang B, et al. HLA ‐A*33‐ DR 3 and A*33‐ DR 9 haplotypes enhance the risk of type 1 diabetes in Han Chinese. J Diabetes Investig. 2016;7(4):514-521. doi: https://doi.org/10.1111/jdi.12462Zhang J. et al. HLA-A*33-DR3 and A*33-DR9 haplotypes enhance the risk of type 1 diabetes in Han Chinese // J. Diabetes Investig. 2016. Vol. 7, № 4. P. 514–521.Koskinen MK, Mikk M-L, Laine A-P, et al. Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies. Diabetes. 2020;69(1):12-19. doi: https://doi.org/10.2337/db19-0329Koskinen M.K. et al. Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies // Diabetes. 2020. Vol. 69, № 1. P. 12–19.Nakanishi K, Inoko H. Combination of HLA-A24, -DQA1*03, and -DR9 Contributes to Acute-Onset and Early Complete β-Cell Destruction in Type 1 Diabetes. Diabetes. 2006;55(6):1862-1868. doi: https://doi.org/10.2337/db05-1049Nakanishi K., Inoko H. Combination of HLA-A24, -DQA1*03, and -DR9 Contributes to Acute-Onset and Early Complete β-Cell Destruction in Type 1 Diabetes // Diabetes. 2006. Vol. 55, № 6. P. 1862–1868.Inshaw JRJ, Cutler AJ, Crouch DJM, Wicker LS, Todd JA. Genetic variants predisposing most strongly to type 1 diabetes diagnosed under age 7 years lie near candidate genes that function in the immune system and in pancreatic B-cells. Diabetes Care. 2020. doi: https://doi.org/10.2337/dc19-0803Inshaw J.R.J. et al. Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells // Diabetes Care. 2020. Vol. 43, № 1. P. 169–177.Nejentsev S, Howson JMM, Walker NM, et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature. 2007;450(7171):887-892. doi: https://doi.org/10.1038/nature06406The Wellcome Trust Case Control Consortium et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A // Nature. 2007. Vol. 450, № 7171. P. 887–892.Besser REJ, Bell KJ, Couper JJ, et al. ISPAD Clinical Practice Consensus Guidelines 2022: Stages of type 1 diabetes in children and adolescents. Pediatr Diabetes. 2022;23(8):1175-1187. doi: https://doi.org/10.1111/pedi.13410Besser R.E.J. et al. Clinical Practice Consensus Guidelines 2022: Stages of type 1 diabetes in children and adolescents // Pediatr. Diabetes. 2022. Vol. 23, № 8. P. 1175–1187.Romanenkova EM, Eremina IA, Titovich EV, et al. C-peptide levels and the prevalence of islets autoantibodies in children with type 1 diabetes mellitus with different duration of the disease. Diabetes mellitus. 2022;25(2):155-165. (In Russ.) doi: https://doi.org/10.14341/DM12843Romanenkova E.M., Eremina I.A., Titovich E.V., Sechko E.A., Nikankina L.V., Peterkova V.A., Bezlepkina O.B., Laptev D.N. C-peptide levels and the prevalence of islets autoantibodies in children with type 1 diabetes mellitus with different duration of the disease. Diabetes mellitus. 2022;25(2):155-165. (In Russ.) https://doi.org/10.14341/DM12843Roep BO, Thomaidou S, van Tienhoven R, Zaldumbide A. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?). Nat Rev Endocrinol. 2021;17(3):150-161. doi: https://doi.org/10.1038/s41574-020-00443-4Roep B.O. et al. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?) // Nat. Rev. Endocrinol. 2021. Vol. 17, № 3. P. 150–161.Gorus FK, Balti E V., Messaaoui A, et al. Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and HLA-DQ Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes. Diabetes Care. 2017;40(8):1065-1072. doi: https://doi.org/10.2337/dc16-2228Gorus F.K. et al. Twenty-Year Progression Rate to Clinical Onset According to Autoantibody Profile, Age, and HLA-DQ Genotype in a Registry-Based Group of Children and Adults With a First-Degree Relative With Type 1 Diabetes // Diabetes Care. 2017. Vol. 40, № 8. P. 1065–1072.Vermeulen I, Weets I, Asanghanwa M, et al. Contribution of Antibodies Against IA-2β and Zinc Transporter 8 to Classification of Diabetes Diagnosed Under 40 Years of Age. Diabetes Care. 2011;34(8):1760-1765. doi: https://doi.org/10.2337/dc10-2268Vermeulen I. et al. Contribution of Antibodies Against IA-2β and Zinc Transporter 8 to Classification of Diabetes Diagnosed Under 40 Years of Age // Diabetes Care. 2011. Vol. 34, № 8. P. 1760–1765.Ziegler AG, Rewers M, Simell O, et al. Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children. JAMA. 2013;309(23):2473. doi: https://doi.org/10.1001/jama.2013.6285Ziegler A.G. et al. Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children // JAMA. 2013. Vol. 309, № 23. P. 2473.Hannelius U, Beam CA, Ludvigsson J. Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes. Diabetologia. 2020;63(10):2177-2181. doi: https://doi.org/10.1007/s00125-020-05227-zHannelius U., Beam C.A., Ludvigsson J. Efficacy of GAD-alum immunotherapy associated with HLA-DR3-DQ2 in recently diagnosed type 1 diabetes // Diabetologia. 2020. Vol. 63, № 10. P. 2177–2181.Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019. doi: https://doi.org/10.1056/nejmoa1902226Herold K.C. et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes // N. Engl. J. Med. 2019. Vol. 381, № 7. P. 603–613.

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