Acta NaturaeActa NaturaeActa Naturae2075-8251Acta Naturae Ltd2785510.32607/actanaturae.27855Research ArticlesЭкспериментальные статьиResearch ArticleGenetic determinants of cellular homeostasis contributing to the risk of type 2 diabetesГенетические детерминанты клеточного гомеостаза и риск сахарного диабета 2 типаTimashevaY. R.ТимашеваЯ. Р.
Russian Federation
yartimasheva@bashgmu.ruKochetovaO. V.КочетоваО. В.
Russian Federation
yartimasheva@bashgmu.ruNasibullinT. R.НасибуллинT. Р.
Russian Federation
yartimasheva@bashgmu.ruKochetovaT. M.КочетоваТ. М.
Russian Federation
yartimasheva@bashgmu.ruBalkhiyarovaZ. R.БалхияроваЖ. Р.
Russian Federation

Section of Statistical Multi-Omics, Department of Clinical & Experimental Medicine, School of Biosciences & Medicine

Секция статистической мультиомики, кафедра клинической и экспериментальной медицины, Школа биологических наук и медицины

yartimasheva@bashgmu.ruKorytinaG. F.КорытинаГ. Ф.
Russian Federation
yartimasheva@bashgmu.ruNouwenA.НоуэнА.
United Kingdom

Department of Psychology

кафедра психологии

yartimasheva@bashgmu.ruInstitute of Biochemistry and Genetics, Ufa Federal Research Centre, Russian Academy of SciencesИнститут биохимии и генетики – обособленное структурное подразделение ФГБНУ «Уфимский федеральный исследовательский центр Российской академии наук»Bashkir State Medical UniversityБашкирский государственный медицинский университетUniversity of SurreyУниверситет СурреяMiddlesex UniversityУниверситет Мидлсекса230720261821081151710202505022026Copyright ©; 2026, Timasheva Y.R., Kochetova O.V., Nasibullin T.R., Kochetova T.M., Balkhiyarova Z.R., Korytina G.F., Nouwen A.Copyright ©; 2026, Тимашева Я.Р., Кочетова О.В., Насибуллин T.Р., Кочетова Т.М., Балхиярова Ж.Р., Корытина Г.Ф., Ноуэн А.2026Timasheva Y.R., Kochetova O.V., Nasibullin T.R., Kochetova T.M., Balkhiyarova Z.R., Korytina G.F., Nouwen A.Тимашева Я.Р., Кочетова О.В., Насибуллин T.Р., Кочетова Т.М., Балхиярова Ж.Р., Корытина Г.Ф., Ноуэн А.https://creativecommons.org/licenses/by/4.0https://actanaturae.ru/2075-8251/article/view/27855

Genetic variation in the genes involved in the maintenance of cellular homeostasis may influence susceptibility to type 2 diabetes (T2D). However, the nature of the interplay among these loci and their prognostic value remains unclear. In this study, we analyzed variants in the FOXO3A, FOXO3, FOXO1, HMOX1, and SIRT1 genes. The HMOX1 rs2071746*T/T genotype was associated with an increased risk of T2D (OR = 1.36, PFDR = 0.030), whereas the FOXO1 rs9549240 (OR = 0.52, PFDR = 0.002) and SIRT1 rs3758391 (OR = 0.80, PFDR = 0.015) genotypes exhibited a protective effect. We detected nonlinear interactions, including FOXO1 rs9549240*G + SIRT1 rs3758391*T + SIRT1 rs7895833*A and HMOX1 rs2071746*A + SIRT1 rs3758391*T + SIRT1 rs7895833*A, with significant synergistic effects (SF = 3.19 and 2.56, P < 0.03). Models incorporating these interactions achieved an AUC of 69.8%, which increased to 86.2% when combined with age, sex, and the body mass index. These findings suggest that interactions between the pathways regulating oxidative stress and metabolism may contribute to the genetic predisposition to T2D.

Генетическая вариабельность в генах, участвующих в поддержании клеточного гомеостаза, может влиять на восприимчивость к сахарному диабету 2 типа (СД2), однако характер взаимодействий между такими локусами и их прогностическая значимость остаются недостаточно изученными. В представленной работе проанализированы варианты генов FOXO3A, FOXO3, FOXO1, HMOX1 и SIRT1. Установлено, что генотип HMOX1 rs2071746*T/T ассоциирован с повышенным риском СД2 (OR = 1.36, PFDR = 0.030), тогда как FOXO1 rs9549240 (OR = 0.52, PFDR = 0.002) и SIRT1 rs3758391 (OR = 0.80, PFDR = 0.015) связаны с защитным эффектом. Обнаружены нелинейные взаимодействия, включая комбинации FOXO1 rs9549240G + SIRT1 rs3758391T + SIRT1 rs7895833*A и HMOX1 rs2071746A + SIRT1 rs3758391T + SIRT1 rs7895833*A, обладающие значимым синергическим эффектом (SF = 3.19 и 2.56, P < 0.03). Модели, основанные на этих взаимодействиях, обеспечивали AUC 69.8%, а добавление возраста, пола и индекса массы тела повышало точность до 86.2%. Полученные данные свидетельствуют о возможном участии взаимодействий между путями регуляции окислительного стресса и метаболизма в формировании генетической предрасположенности к СД2.

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