mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-3-441-450mimmun-1817Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESПОЛИМОРФИЗМ ГЕНОВ ВНЕКЛЕТОЧНЫХ ПРОТЕИНАЗ РЕМОДЕЛИРОВАНИЯ СОЕДИНИТЕЛЬНОЙ ТКАНИ (MMP2, MMP3, MMP9) И ГЕНА НЕОАНГИОГЕНЕЗА (VEGF) ПРИ МИКРОАНГИОПАТИЯХ СЕТЧАТКИ ГЛАЗА У ПАЦИЕНТОВ С САХАРНЫМ ДИАБЕТОМ 2 ТИПАPOLYMORPHISMS OF EXTRACELLULAR CONNECTIVE TISSUE REMODELING PROTEINASES AND MMP2, MMP3, MMP9 GENES, AND NEOANGIGENESIS VEGF GENE IN RETINAL MICROANGIOPATHY IN THE PATIENTS WITH TYPE 2 DIABETES MELLITUSШевченкоА. В.ShevchenkoA. V.

д.б.н., ведущий научный сотрудник лаборатории клиничеcкой иммуногенетики

630060, г. Новосибирск, ул. Тимакова, 2.Тел.: 8 (952) 901-36-80.

PhD, MD (Biology), Leading Research Associate, Laboratory of Clinical Immunogenetics

630060, Novosibirsk, Timakova str., 2.Phone: 7 (952) 901-36-80.

shalla64@mail.ruПрокофьевВ. Ф.ProkofievV. F.

к.м.н., ведущий научный сотрудник лаборатории клинической иммуногенетики

г. Новосибирск

PhD (Medicine), Senior Research Associate, Laboratory of Clinical Immunogenetics

Novosibirsk

КоненковВ. И.KonenkovV. I.

д.м.н., профессор, академик РАН, руководитель лаборатории клинической иммуногенетики

г. Новосибирск

PhD, MD (Medicine), Professor, Full Member, Russian Academy of Sciences, Head, Laboratory of Clinical Immunogenetics

Novosibirsk

КлимонтовВ. В.KlimontovV. V.

д.м.н., профессор РАН, заведующий лабораторией эндокринологии, заместитель руководителя филиала по научной работе

г. Новосибирск

PhD, MD (Medicine), Professor, Russian Academy of Sciences, Head, Laboratory of Endocrinology, Deputy Director for Science

Novosibirsk

ТянН. В.TyanN. V.

младший научный сотрудник лаборатории эндокринологии

г. Новосибирск

Junior Research Associate, Laboratory of Endocrinology

Novosibirsk

ЧерныхД. В.ChernykhD. V.

к.м.н., врач-офтальмолог 

г. Новосибирск

PhD (Medicine), Ophthalmologist

Novosibirsk

ТруновА. Н.TrunovA. N.

д.м.н., профессор, заместитель директора по научной работе

г. Новосибирск

PhD, MD (Medicine), Professor, Deputy Director for Research

Novosibirsk

ЧерныхВ. В.ChernykhV. V.

д.м.н., профессор, директор

г. Новосибирск

PhD, MD (Medicine), Professor, Director

Novosibirsk

Научно-исследовательский институт клинической и экспериментальной лимфологии – филиал ФГБНУ «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук»РоссияResearch Institute of Clinical and Experimental Lymрhology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of SciencesRussian FederationФГБУ «МНТК „Микрохирургия глаза“ имени академика С.Н. Федорова» Министерства здравоохранения РФ, Новосибирский филиалРоссияNovosibirsk Branch of the S. Fyodorov Intersectoral Research and Technology Complex “Eye microsurgery”Russian Federation201912072019213441450Copyright © Шевченко А.В., Прокофьев В.Ф., Коненков В.И., Климонтов В.В., Тян Н.В., Черных Д.В., Трунов А.Н., Черных В.В., 20192019Шевченко А.В., Прокофьев В.Ф., Коненков В.И., Климонтов В.В., Тян Н.В., Черных Д.В., Трунов А.Н., Черных В.В.Shevchenko A.V., Prokofiev V.F., Konenkov V.I., Klimontov V.V., Tyan N.V., Chernykh D.V., Trunov A.N., Chernykh V.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.mimmun.ru/mimmun/article/view/1817

Целью исследования являлся анализ ассоциированности полиморфизма генов MMP2, MMP3, MMP9, VEGF с развитием непролиферативной диабетической ретинопатии (ДР) у пациентов с сахарным диабетом 2 типа (СД2).

В исследование включен 201 пациент с СД2. Среди них 90 человек с ДР и 111 человек без признаков ДР. Исследовали полиморфизм генов MMP2 (rs2438650), MMP3 (rs3025058), MMP9 (rs3918242) и VEGF (rs699947 и rs3025039). Генотипирование осуществляли методом анализа полиморфизма длин рестрикционных фрагментов и методом TaqMan-зондов.

При анализе комплексных генотипов пяти полиморфных позиций выявлена определенная закономерность в позитивно и негативно объединенных комплексах. Показано увеличение частоты CC генотипа в полиморфной позиции - 1306 гена MMP2 в группе пациентов с «ранним» развитием осложнения и повышение у пациентов с наличием ДР комбинации высокого уровня HbA1 c генотипами MMP2-1306CC и MMP9-1562CT. Компьютерное моделирование с визуальной реконструкцией сетевых взаимодействий генотипов, вовлеченных в регуляцию деструкции и ангиогенеза, и уровней HbA1с-продукции – интегрального показателя гликемии – выявило наличие различий в структурно-функциональной организации ген-генных и ген-белковых взаимодействий в группах больных с наличием и отсутствием ДР.

Построение интерактомных биологических сетей транскрипционной регуляции и метаболических путей и их топологический анализ позволяют строить и изучать генные и белковые взаимодействия применительно к исследованию патогенеза осложнений СД 2 типа для разработки в последующем подходов к персонифицированной профилактике и терапии.

The aim of our study was to perform an association analysis between MMP2, MMP3, MMP9, VEGF gene polymorphisms and development of non-proliferative diabetic retinopathy (DR) in the type 2 diabetic patients (DM).

201 DM patients: 90 cases of DR and 111 subjects without DR features were included into the study. Polymorphic variants of MMP2 (rs2438650), MMP3 (rs3025058), MMP9 (rs3918242), and VEGF (rs699947 and rs3025039) genes were assayed. The genetic typing was carried out by restriction fragment length polymorphism and TaqMan methods.

The analysis of complex genotypes at the five polymorphic positions has revealed some significant findings in positive and negatively incorporated complexes. Increased frequencies of MMP2-1306 CC genotype in the group of patients with “early” development of complication, and more frequent combination of high-level HbA1c with MMP2-1306CC and MMP9-1562CT genotypes were shown in DR patients. Computerassisted modelling with visual reconstruction of network interactions between the genotypes involved into the destruction events and angiogenesis, as well as altered HbA1с levels (an integral parameter of glycemia), has revealed some differences in structural and functional organization of gene-gene and gene- protein interactions between the groups of patients with DR versus those without this disorder. Сonclusion. A design of interactome biological networks based on transcription regulation and metabolic pathways, as well as their topological analysis allows to build and study interactions of genes and proteins, with reference to pathogenetic studies of DM2 complications aiming for development of approaches to personalized prevention and therapy in future times.

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