vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-29vavilov-5038Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSНовые регуляторные однонуклеотидные полиморфизмы (rSNPs) потенциально участвуют в регуляции глюконеогенеза в печени и вносят вклад в вариабельность АМФК¬зависимых механизмов индивидуального ответа на метформинNovel regulatory SNPs that can be activated due to metformin treatment may orchestrate liver gluconeogenesis and add to the variability in AMPK-dependent mechanisms of metformin responseКорболинаЕ. Е.KorbolinaE. E.

Новосибирск

Novosibirsk

lungry@bionet.nsc.ruДамаровИ. С.DamarovI. S.

Новосибирск

Novosibirsk

МеркуловаТ. И.MerkulovaT. I.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202606042026302259266Copyright © Корболина Е.Е., Дамаров И.С., Меркулова Т.И., 20262026Корболина Е.Е., Дамаров И.С., Меркулова Т.И.Korbolina E.E., Damarov I.S., Merkulova T.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5038

Метформин является препаратом первого выбора для лечения сахарного диабета второго типа, однако более чем у 30 % пациентов не достигается оптимальный гликемический контроль. Лежащие в основе этого феномена регуляторные механизмы и ассоциированные генетические варианты остаются неизученными. Накопленные данные свидетельствуют о том, что ключевую роль в определении фенотипической вариабельности играют функциональные генетические варианты, в особенности регуляторные однонуклеотидные полиморфизмы (rSNP), непосредственно влияющие на уровень экспрессии генов. Полногеномный поиск таких функциональных вариантов и выявление их фенотипических последствий – актуальная научная задача. Ранее на основе результатов биоинформатического анализа аллель-специфической экспрессии и профиля распределения активирующих гистоновых модификаций в мононуклеарных клетках периферической крови человека нами была сформирована оригинальная панель из 14 796 rSNP, локализованных в промоторах 5132 генов. Целью настоящей работы был поиск в нашей панели rSNP вариантов, потенциально связанных с регуляцией процессов глюконеогенеза в печени, в том числе под действием монотерапии метформином, с помощью анализа независимых релевантных полногеномных данных. Анализировали 1196 генов, экспрессия которых в гепатоцитах человека изменялась под влиянием метформина АМФК-зависимым образом, а также 115 генов, вовлеченных в глюконеогенез и/или его регуляцию, согласно данным генных онтологий. Для функциональной аннотации использовали инструменты свободного программного обеспечения R и базы данных STRING (v.11). В результате анализа был выделен ряд генов, которые, вероятно, играют особую роль в механизмах действия метформина и индивидуальной чувствительности к препарату, в промоторных районах которых нами были картированы rSNP. Функциональный анализ обогащения выявил вовлеченность этих генов в ключевые сигнальные пути, ассоциированные также с осложнениями сахарного диабета второго типа. Для шести генов (ARPP19, ATF4, NR3C1, PFKFB3, TCF7L2 и WDR5) экспрессия не только тесно связана с регуляцией глюконеогенеза, но также может модулироваться в гепатоцитах под действием метформина. Мы предполагаем, что rSNP в промоторах генов ферментов, участвующих в глюконеогенезе, и транскрипционных факторов могут играть существенную роль в механизмах формирования индивидуального ответа на терапию метформином.

Metformin is a first-line therapy for type 2 diabetes, yet individual response varies significantly, with over 30 % of patients failing to achieve optimal glycemic control. The specific regulatory mechanisms of this phenomenon remain poorly understood and genetic variants involved are mainly undiscovered. There are multiple lines of evidence that the leading role in determining the variance in phenotypic outcome belongs to regulatory SNPs (rSNPs) as they directly modify gene expression. Therefore, the genome-wide search for such functional variants and deciphering associated phenotypes stands as a fundamental challenge. Previously, based on the results of bioinformatics analysis of allele-specific expression and binding landscape in human peripheral blood mononuclear cells, we have established an original panel of 14 796 rSNPs within promotors of 5132 genes. Aiming to pinpoint functional variants most likely linked to metformin hepatic response and impacts on liver gluconeogenesis, we analyzed the relevant open-access data as well as rSNPs from our panel and the corresponding genes. 1196 genes reported to be regulated by metformin in human hepatocytes and 115 genes involved in gluconeogenesis and/or its regulation via Gene Ontology annotations were intersected. Free R software and STRING v.11 tools were used for functional annotation. A number of genes harboring rSNPs within promotor regions were found to be particularly implicated in the mechanisms of metformin’s action. Functional enrichment analyses revealed enrichment in critical pathways including FoxO, TNF-α and TGF-β signaling, also implicated in diabetes complications. Among these, six genes (ARPP19, ATF4, NR3C1, PFKFB3, TCF7L2, and WDR5) were strongly associated with regulation of gluconeogenesis, and may be modulated by metformin in the liver. We conclude that metformin therapy response may be influenced by the newly identified functional SNPs including rSNPs within the promotors of genes for gluconeogenic enzymes and transcription regulators.

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