medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2021.01.25-36medgen-1839Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHПолиморфный вариант rs4430796 гена HNF1B: пол-специфические, ИМТ-зависимые ассоциации с показателями метаболизма глюкозы, редокс-гомеостаза и риском сахарного диабета 2 типаPolymorphic variant rs4430796 at HNF1B gene: sex-specific, BMI-dependent associations with parameters of glucose metabolism, redox homeostasis and risk of type 2 diabetesАзароваЮ. Э.AzarovaIu. E.azzzzar@yandex.ruКлёсоваЕ. Ю.KlyosovaE. Yu.noemail@neicon.ruПолониковА. В.PolonikovA. V.noemail@neicon.ruФГБОУ ВО «Курский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияKursk State Medical UniversityRussian Federation2021110320212012536Copyright © Азарова Ю.Э., Клёсова Е.Ю., Полоников А.В., 20212021Азарова Ю.Э., Клёсова Е.Ю., Полоников А.В.Azarova I.E., Klyosova E.Y., Polonikov A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/1839

Ожирение является важнейшим фактором риска развития сахарного диабета 2 типа (СД2). Гепатоцитарный ядерный фактор 1 β (HNF1B) контролирует глюкостатическую функцию островков Лангерганса поджелудочной железы и ассоциирован с развитием СД2 в европейской и азиатской популяциях. Однако исследований, оценивающих роль генетических вариантов HNF1B в формировании предрасположенности к СД2 в русской популяции, на сегодняшний день не проводилось. Целью настоящей работы стало изучение ассоциации полиморфного варианта rs4430796 (A>G) в интроне гена HNF1B с показателями гликемического профиля и редокс-гомеостаза, а также риском развития СД2 у жителей Центральной России, с учетом их пола и индекса массы тела. В исследование включено 3206 человек, из них 1579 больных СД2 и 1627 условно здоровых добровольцев. Генотипирование проводили с использованиеми технологии iPLEX на геномном времяпролетном масс-спектрометре MassArray 4 (Agena Bioscience). Впервые в русской популяции установлена взаимосвязь полиморфизма rs4430796 гена HNF1B с повышенным риском развития СД2 (OR 1,24, 95CI 1,05-1,47, р=0,011). Стратифицированный анализ по полу обнаружил, что выявленная ассоциация характерна только для женщин с избыточной массой тела (OR 1,54, 95CI 1,06-2,22, р=0,02) и ожирением (OR 2,07, 95CI 1,14-3,77, р=0,047) и отсутствует у лиц с нормальной массой тела вне зависимости от пола. Изучаемый SNP ассоциирован с повышенным содержанием перекиси водорода (р=0,012) и более низким уровнем общего глутатиона плазмы (р=0,041) у женщин, тогда как у мужчин с СД2 генотип G/G связан со снижением концентрации С-пептида (р=0,004) и повышением концентрации глюкозы крови (р=0,015). Биоинформатический анализ подтвердил отрицательный эффект аллеля G на экспрессию HNF1B, а также выявил его связь с гиперметилированием гена в различные периоды жизни, что обусловливает низкую экспрессию гена HNF1B у носителей минорного аллеля rs4430796-G. Таким образом, нами впервые установлено, что полиморфный вариант гена HNF1B rs4430796 ассоциирован с предрасположенностью к СД2 в русской популяции, при этом его связь с заболеванием имеет пол-специфический характер и зависит от индекса массы тела.

Obesity is a critical risk factor for type 2 diabetes mellitus (T2D). Hepatic nuclear factor 1 β (HNF1B) controls the glucostatic function of pancreatic islets of Langerhans and is associated with the development of T2D in the European and Asian populations. However, studies evaluating the contribution of genetic variants at HNF1B to the pathogenesis of the disease in Russian population have not been conducted to date. The aim of this work was to study the association of the polymorphic variant rs4430796 (A>G) in the intron of the HNF1B gene with parameters of glycemic profile and redox homeostasis, as well as the risk of developing T2D in citizens of Central Russia, taking into account their gender and body mass index. The study included 3206 participants, 1579 patients with T2D and 1627 healthy volunteers. Genotyping was performed using iPLEX technology on a genomic time-of-flight mass spectrometer MassArray 4 (Agena Bioscience). For the first time in the Russian population, the relationship of the rs4430796 polymorphism at the HNF1B gene with an increased risk of developing T2D (OR 1,24, 95CI 1,05-1,47, p=0,011) was established. A gender-stratified analysis found that the association is characteristic only for females with overweight (OR 1,54, 95CI 1,06-2,22, p=0,02) and obesity (OR 2.07, 95CI 1,14-3,77, p=0.047) and is absent in individuals with normal body weight, regardless from the gender. The studied SNP is associated with an increased content of hydrogen peroxide (p=0,012) and a lower level of total plasma glutathione (p=0,041) in females, whereas in diabetic males the G/G genotype is associated with a decrease in the concentration of C-peptide (p=0,004) and an increase in blood glucose concentration (p=0,015). Bioinformatic analysis confirmed the negative effect of the alternative G allele on the expression of the HNF1B gene, as well as its relationship with hypermethylation of the gene at different periods of life, which leads to low expression of HNF1B in carriers of variant rs4430796. Conclusions: It was found for the first time that the polymorphic variant rs4430796 of the HNF1B gene is associated with a predisposition to T2D, whereas its relationship with the disease is sex-specific and depends on body mass index.

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