Nikulina A. Differentiated approach to the management of children with different phenotypes of obesity associated with chronic low-level inflammation

Українська версія

Thesis for the degree of Doctor of Science (DSc)

State registration number

0524U000434

Thesis Registration Form

0524U000434.pdf

Applicant for

Anna Nikulina

Specialization

14.01.10 - Педіатрія

Date of defense

10-12-2024

Specialized Academic Board

Д26.553.01

State institution «Ukrainian center of maternity and childhood of the National academy of medical sciences of Ukraine»

Essay

To achieve the set goal and solve the research tasks, we examined 500 children aged 6-18 years, of which 350 children with obesity and 100 children with type 1 diabetes were treated. The control group was represented by 50 non-obese children. Among children with obesity, whose body mass index exceeded the 95th percentile according to the recommendations of the IDEFICS consortium, two observation groups with MHO and MUO were distinguished, which were subject to one-year catamnetic observation to determine a personalized prognosis of obesogenic consequences, taking into account the individual characteristics of the genotype and a differentiated algorithm for the management of children with obesity based on the assessment of the diagnostic value of clinical genetic markers and the analysis of the effectiveness of the comprehensive interdisciplinary weight management program (weight management program - WMP) and pharmacotherapy (anti-obesity medications - AOM) on the effectiveness of the treatment of obesity in children. Children with newly diagnosed type 1 diabetes (n=100) with obesity and BMI not exceeding the 85th percentile were subject to one-year follow-up to build a mathematical model for predicting the uncontrolled course of type 1 diabetes. Based on the screening of genomes and the study of single nucleotide variants (SNVs) of genes, the genotypes of candidate genes responsible for the formation of metabolomes with characteristic pathophysiological pathways of diabetes, which determine the risk of the formation of a progressive loss of adequate insulin secretion by β-cells, often against the background of insulin resistance, were identified. , and also developed a mathematical model for predicting the uncontrolled course of type 1 autoimmune diabetes (absolute insulin deficiency). An algorithm for predicting metabolically unhealthy obesity in children was developed by identifying target groups of patients who carry cluster associations of single-nucleotide variants of genes associated with taste preferences: the CG SNV rs713598 genotype of the taste 2 receptor member 38 gene (TAS2R38); affecting appetite: genotype TT SNV rs3790435 of the leptin receptor gene (LEPR), genotype AT SNV rs4684677 of the ghrelin gene (GHRL); genotypes GA SNV rs3765468, СC rs1042044 of the glucagon-like peptide 1 receptor (GLP1R) gene, genotype GG SNV rs754635 of the cholecystokinin gene (CСK); affecting adipogenesis and lipid status: genotypes AG rs2287142, CC rs17823223 of the gene associated with fat mass and obesity-associated (FTO), genotype ST SNV rs1800139 of the protein gene related to the low-density lipoprotein receptor type 1 (LRP1), genotypes CG SNV rs738409, CT SNV rs738408, GA SNV rs4823173 and AG SNV rs2072906 of the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3); associated with chronic low-level inflammation: genotypes AG SNV rs12721365, rs2228572 of the vitamin D receptor (VDR) gene, genotypes AG rs3213891, GA rs3213890, CT rs3754689 of the lactase gene (LCT) and genotype GA rs1057031 of the minichromosomal maintenance component gene 6 (MCM6). Developed methods of predicting the uncontrolled course of type 1 diabetes and metabolically unhealthy obesity, the effectiveness of treatment of children with various phenotypes of obesity allow to improve the tactics of managing such children. The high efficiency of our proposed algorithms made it possible to implement them in the practice of medical and preventive institutions. Analysis of effectiveness demonstrates that the strategy of searching for new markers - candidates in the pathogenesis of low-level inflammation in obesity and its associated complications in the children population allows to reduce the metabolic risk of morbidity for the mentioned diseases by predicting it at the early diagnostic stage, to personalize therapy and, in general, to prevent threatening life is complicated. The high efficiency of our proposed algorithms made it possible to implement them in the practice of medical and preventive institutions. It is the differentiated approach to the management of children with various phenotypes of obesity, the improvement of immunological and metabolic health among the "high-risk" group for diabetes, the improvement of personalized management of patients with obesity and associated complications, the prevention of disability from childhood, and the condition of medical and social relevance of this problem.

Official opponents

Liudmyla Omelchenko
Oleksandr Volosovets
Haiane Akopian

Research papers

1. Абатуров О.Є., Нікуліна А.О. Метаболічно асоційована жирова хвороба печінки у дітей: монографія. Дніпро. «Ліра», 2021:780.

2. Абатуров О.Є., Нікуліна А.О., Кривуша О.Л., Алейнікова Т.Д. Генотип – асоційована персоніфікація діагностичного пошуку при ожирінні у дітей із генотипами гена лактази. Світ медицини та біології. 2018; 4 (66): 9-14.

3. Abaturov A., Stepanov Yu., Nikulina A. Treatment of lactase deficiency in children’s obesity with genotype C/C 13910 of lactase gene. Wiadomości Lekarskie. 2019; 1 (72): 17-21.

4. Abaturov A., Nikulina A. Genotype C/C 13910 of the Lactase Gene as a Risk Factor for the Formation of Insulin-Resistant Obesity in Children. Acta Medica (Hradec Králové) 2019; 62(4): 150–155. doi.org/10.14712/18059694.2020.4.

5. Абатуров О.Є., Нікуліна А.О., Петренко Л.Л., Єнговатова В.А., Турова С.В., Макогон І.М. Прогнозування неконтрольованого перебігу автоімунного цукрового діабету 1 типу у дітей. Здоров’я дитини. 2020; 2 (15): 6-15.

6. Абатуров О.Є., Нікуліна А.О. Порушення харчової поведінки при різних фенотипах ожиріння у дітей. Здоров’я дитини. 2020; 5 (15); 55-59.

7. Abaturov A.E., Nikulina A.O. Association of leptin receptor gene polymorphisms and meta-inflammation markers with metabolically unhealthy obesity in children. Запорізький медичний журнал. 2021; Vol. 23; 5(123):696-702

8. Abaturov A., Nikulina A. Obesity in Children with Leptin Receptor Gene Polymorphisms. Acta Medica (Hradec Králové). 2021; 64(3): 158–164.

9. Abaturov А., Nikulina А. Taste preferences and obesity. Pediatria Polska - Polish Journal of Paediatrics. 2022;97(1):1-6.

10. Abaturov А., Nikulina А. Role of genetic modification of the PNPLA3 gene in predicting metabolically unhealthy obesity and associated fatty liver disease in hildren. Eur J Clin Exp Med. 2023;21(1):5–13.

11. Abaturov A, Nikulina A. Functional annotation of lactase gene and its distal enhancer MCM6 for prediction of metabolically unhealthy obesity. Pediatria Polska - Polish Journal of Paediatrics. 2023;98(1):16-22.

Abaturov А, Nikulina А. The role of vitamin D in metabolically unhealthy obesity in children. Здоров’я дитини. 2023; 18(2):29-35. doi.org/10.22141/2224-0551.18.2.2023.1568.

13. Abaturov A., Nikulina A. Genetically determined vitamin D reception in metabolically unhealthy obesity in children. Здоров’я дитини. 2023;18(3):22-28.

14. Abaturov A., Nikulina A. Associations of GHRL gene variants with the development of obesity and metabolic disorders in children. Здоров’я дитини. 2023;18(4):13-19.

Nikulina A. Significance of the rs754635 variant of the cholecystokinin gene in the development of obesity in children. Modern Pediatrics. Ukraine. 2023; 5(133): 17-23.

16. Nikulina A. Genetic variants of the glucagon-like receptor-1 in obesity. Eur J Clin Exp Med. 2023;21(4):682–691.

17. Abaturov A., Nikulina A. Association of genetic variants of the FTO gene and obesity in children. Port J Pediatr. 2024;55(2):89-97.

18. Nikulina A.O. Significance of single-nucleotide variants of anorexigenic hormone genes in childhood obesity. Medicni perspektivi. 2024;29(1):108-114.

19. Abaturov O.Ye., Nikulina A.O. Single-nucleotide variant rs1800139 of the LRP1 gene as a factor in the development of obesity in children. Modern Pediatrics. Ukraine. 2024; 3(139): 10-17.

20. Abaturov A., Nikulina A. Model for predicting the outcome of the weight management program. Проблеми клінічної педіатрії. 2024; 2(64): 22-32.

21. Свідоцтво про реєстрацію авторського права на твір № 112819 від 02.05.2022 р. Ожиріння та розлади харчової поведінки: діагностика, профілактика і терапія / Абатуров О.Є., Юр’єва Л.М., Величко В.І., Кожина Г.М., Крючко Т.О., Леженко Г.О., Агафонова О.О., Бабич В.Л., Зеленська К.О., Кокашинський В.О., Нікуліна А.О., Радченко Т.М., Терьошина І.Ф., Токарєва Н.М., Шорніков А.В., Шустерман Т.Й.

22. Свідоцтво про реєстрацію авторського права на твір № 112818 від 02.05.2022 р. Метаболічно асоційована жирова хвороба печінки / Абатуров О.Є., Нікуліна А.О.

23. Абатуров О.Є., Нікуліна А.О. Коморбідні стани при ожирінні у дітей. Охорона здоров’я дітей та підлітків. Український міжвідомчий збірник 2022; 1: 9-12.

24. Nikulina A. Association of single-nucleotide variants of the glucagon-like peptide-1 receptor gene with sweet taste preferences in children with obesity. Охорона здоровя дітей та підлітків. Український міжвідомчий збірник. 2023; 1-2: 92-95.

25. Abaturov A.Е., Nikulina A.O., Petrenko L.L., Sova D.Yu. Stratification of controlled course of autoimmune diabetes mellitus as a low-level inflammation in children. Topical issues of the development of modern science. Publishing House “Accent”. Sofia, Bulgaria. 2020:15-21.

26. Abaturov А., Nikulina A., Nikulin D. Eating disorders associated with SNV TAS2R38 in children with obesity. Педіатрія сьогодення. 2022: 99-104.

27. Abaturov A.E., Nikulina A., Kolbasin P. Genetic predictors of metabolic unhealthy obesity in children. Topical issues of science and practice. Publishing House “Accent”. London, Great Britain 2020: 287-292.

28. Abaturov A., Nikulina A., Minko I., Pashkevych S. Genetic variants of taste and obesity. Modernization of science and its influence on global processes. Bern, Swiss Confederation. November 5, 2021; Vol. 2.:69-71.

29. Крючко Т.О., Абатуров О.Є., Пода О.А., Кривуша О.Л., Бубир Л.М., Нікуліна А.О. Ефективність застосування препаратів бетаїн-аргінінового комплексу для профілактики та лікування неалкогольної жирової хвороби печінки у дітей з ожирінням. Перелік наукової (науково-технічної) продукції, призначеної для впровадження досягнень медичної науки у сферу охорони здоров᾽я (Випуск 5). Київ, 2019:258-259. Реєстр. № 271/5/18.

30. Абатуров О.Є., Нікуліна А.О. Спосіб персоніфікованого прогнозування та лікування метаболічно нездорового ожиріння у дітей з лактазною недостатністю. Перелік наукової (науково-технічної) продукції, призначеної для впровадження досягнень медичної науки у сферу охорони здоров’я (Випуск 9). Київ, 2023:123-124. Реєстр. № 83/9/23.

31. Абатуров О.Є., Нікуліна А.О. Варіації смакових уподобань при фенотипах ожиріння у дітей. Неонатологія, хірургія та перинатальна медицина. 2021; Т. ХІ, 3(41):4-5.

32. Абатуров О.Є., Нікуліна А.О. Фенотипи харчової поведінки та формування низькорівневого запалення й інсулінорезистентності. Гастроентерологія, 2020; 4 (54): 95.

33. Abaturov A., Nikulina A. The role of leptin receptor gene polymorphism in the formation of insulin resistance in children. Metabolism Clinical and Experimental. 2021; Volume 116, Supplement, 154672, March 01: 82.

34. Абатуров О.Є., Нікуліна А.О., Мінько І.О., Пашкевич С.С. Роль смакових уподобань в регуляції харчової поведінки у дітей. Новини і перспективи медичної науки: зб. мат. XХІІ конф. студ. та мол. учених: [під ред. Твердохліба І.В., Бондаренко Н.С.]. Дніпро, 2022:51.

Abaturov A., Nikulina A., Nikulin D. TAS2R38 taste receptor gene and metabolically unhealthy obesity. Metabolism Clinical and Experimental. 2022; Volume 128, Supplement, March 01: 155003.

36. Abaturov A., Nikulina A., Nikulin D. Personalized treatment of metabolically unhealthy obesity in children. Український науково-медичний молодіжний журнал. 2022;1 (129):13.

Abaturov A., Nikulina A. The role of single nucleotide variants of the lactase gene and the lactase gene enhancer MCM6 in the development of metabolically unhealthy obesity in children. Collection of materials of the scientific and practical conference with international participation, dedicated to the 100th anniversary of the Tashkent Medical Academy, "100 years of the Tashkent Medical Academy – the era of great achievements and discoveries". "Tibbiyot nashriyoti matbaa uyi" MCHJ Toshkent; 2022: 84.

38. Abaturov A., Nikulina A. Risk of metabolically unhealthy obesity in children associated with lactase and MCM6 genes. Journal of rehabilitation medicine. 2022; 54:16.

39. Абатуров О.Є., Нікуліна А.О. Однонуклеотидні варіанти гена PNPLA3 — генетичні модифікатори метаболічно асоційованої жирової хвороби печінки. Гастроентерологія. 2022; 3(56): 72.

40. Abaturov A., Nikulina A., Nikulin D. Single nucleotide variants of hypoxia-inducible factor-1 associated with Obstructive sleep apnea syndrome in obesity. Ukrainian scientific medical youth journal. 2023.Supplement №1 (137):37-38.

41. Abaturov A., Nikulina A., Nikulin D. Single Nucleotide Variants of the MCM6 Gene as a Risk Factor for Metabolically Unhealthy Obesity in Children. American Heart Journal. 2022; 254:249.

42. Abaturov A., Nikulina A., Nikulin D. Single nucleotide variants of the VDR gene and cardiometabolic risk in obesity American Heart Journal. 2024; January; Volume 267: 116-117.

43. Abaturov A., Nikulina A., Nikulin D. Single Nucleotide Variants of the PNPLA3 Gene Are Important Genetic Modifiers for the Progression of Metabolically Unhealthy Obesity in Children. Metabolism Clinical and Experimental. 2023; Volume 142, Supplement, May 2023: 155450.

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