mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-POV-1913mimmun-1913Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESПолиморфизм генов фактора роста эндотелия сосудов (VEGF) и матриксных металлопротеиназ (ММР) при первичной лимфедеме конечностейPolymorphism of vascular endothelial growth factor gene (VEGF) and matrix metalloproteinase (ММР) genes in primary limb lymphedemahttps://orcid.org/0000-0001-5898-950XШевченкоА. В.ShevchenkoA. V.

Шевченко Алла Владимировна - д.б.н., ведущий научный сотрудник лаборатории клиничеcкой иммуногенетики

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

Shevchenko Alla V., PhD, MD (Biology), Leading Research Associate, Laboratory of Clinical Immunogenetics

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

shalla64@mail.ruhttps://orcid.org/0000-0001-7290-1631ПрокофьевВ. Ф.ProkofyevV. F.

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

г. Новосибирск

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

Novosibirsk

vprok@ngs.ruhttps://orcid.org/0000-0001-7385-6270КоненковВ. 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

vikonenkov@gmail.comhttps://orcid.org/0000-0001-6861-7152ХапаевР. С.KhapaevR. S.

к.м.н., старший научный сотрудник лаборатории оперативной лимфологии и лимфодектоксикации

г. Новосибирск

PhD (Medicine), Senior Research Associate, Laboratory of Surgical Lymphology and Lymphodetoxication

Novosibirsk

https://orcid.org/0000-0002-9889-3729НимаевВ. В.NimaevV. V.

д.м.н., заведующий лабораторией оперативной лимфологии и лимфодектоксикации

г. Новосибирск

PhD, MD (Medicine), Head, Laboratory of Surgical Lymphology and Lymphodetoxication

Novosibirsk

nimaev@gmail.comНаучно-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, Institute of Cytology and Genetics, Siberian Branch, Russian Academy of SciencesRussian Federation202020052020223497506Copyright © Шевченко А.В., Прокофьев В.Ф., Коненков В.И., Хапаев Р.С., Нимаев В.В., 20202020Шевченко А.В., Прокофьев В.Ф., Коненков В.И., Хапаев Р.С., Нимаев В.В.Shevchenko A.V., Prokofyev V.F., Konenkov V.I., Khapaev R.S., Nimaev 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/1913

Среди причин развития первичной лимфедемы (ПЛ) определенное значение играют генетические факторы, молекулярные продукты которых участвуют в процессах ремоделирования кровеносных и лимфатических сосудистых сетей. Сосудистые эндотелиальные факторы роста (VEGFs) – ключевые регуляторы эндотелиальной функции клеток, ответственных за лимфо-, васкуло- и ангиогенез. Кроме того, регуляторами и лимфангиогенеза, и ангиогенеза могут выступать матриксные металлопротеиназы (ММР). Поскольку регуляторные регионы гена, кодирующего VEGF-A, как и регуляторные регионы генов ММР, полиморфны, возможно, что различный уровень их экспрессии, определяемый полиморфизмом этих регионов, может быть ассоциирован с развитием отеков, свойственных лимфедеме. Проанализирован полиморфизм двух регуляторных регионов гена фактора роста эндотелия сосудов VEGF-A (rs 699947 и rs 3025039) и полиморфизм промоторных регионов генов матриксных металлопротеиназ MMP2 (rs 2438650), MMP3 (rs 3025058), MMP9 (rs 3918242) и их комбинаций у пациентов с первичной лимфедемой.

Выборка пациентов с первичной лимфедемой конечностей включала 72 человека (55 женщин и 17 мужчин) в возрасте от 18 до 81 года, в популяционную группу контроля включены 526 жителей г. Новосибирска (153 мужчины, 373 женщины) без хронических заболеваний, сопоставимые по возрасту с выборкой больных лимфедемой. Проведено типирование регуляторных регионов генов VEGF (rs 699947, rs 3025039), ММР2 (rs 2438650), ММР3 (rs 3025058), ММР9 (rs 3918242). Выявлено 15 комплексных генотипов, позитивно ассоциированных с заболеванием. Анализ топологии генной сети выделил главные межгенные взаимодействия при развитии первичной лимфедемы. MMP2 - 1306 CC, MMP9 -1562 CC и VEGF +936 CC формируют основные узлы в генной сети (53% от всех взаимодействий). Выявлен ряд достоверно различающихся комплексных генотипов у пациентов с ПЛ с нормальным индексом массы тела (ИМТ) (менее 25) и ожирением (ИМТ более 30). Так, частота комплексного генотипа VEGF +936 CC:MMP3 -1171 5А6А:MMP9 -1562 CC у пациентов с ожирением повышена более чем в пять с половиной раз относительно пациентов с нормальным ИМТ.

Полученные данные могут свидетельствовать об определенном значении полиморфизма анализируемых генов на патогенез развития первичной лимфедемы конечностей. Tопологический анализ генных сетей позволяет изучать структурно-функциональную организацию ген-генных взаимодействий для разработки подходов к персонифицированной профилактике и терапии заболевания.

Among the reasons of primary lymphedema development, a certain role belongs to genetic factors. The specific molecular products participate in remodeling of blood and lymphatic vascular networks. Vascular endothelial growth factors (VEGFs) are key regulators of endothelial functions of the cells, which are responsible for lympho- and vasculogenesis. Moreover, matrix metalloproteinases (ММР) may act as regulators of both lymphangiogenesis, and angiogenesis. Since the regulatory regions of VEGFA gene, as well as of ММР genes are polymorphic, one may suggest, that their different expression level, determined by these polymorphisms, could be associated with development of swellings typical for lymphedema.

We have analyzed gene polymorphisms in two regulatory regions of vascular endothelial growth factor-A VEGF-A (rs 699947 and rs 3025039), and matrix metalloproteinase genes MMP2 (rs 2438650), MMP3 (rs 3025058), MMP9 (rs 3918242), and their combinations in the patients with primary lymphedema.

A group of patients with primary lymphedema included 72 subjects (55 women and 17 men) at the age of 18 to 81 years. Control group included 526 inhabitants of Novosibirsk (153 men, 373 women) without chronic diseases, comparable for age with lymphedema patients. We have performed typing of regulatory regions in VEGF (rs 699947, rs 3025039), ММР2 (rs 2438650), ММР3 (rs 3025058), ММР9 genes (rs 3918242). Fifteen complex genotypes have been revealed that were positively associated with disease. Analysis of the gene network topology has outlined the main intergenic interactions upon primary lymphedema development. MMP2 -1306 CC, MMP9 -1562CC and VEGF +936CC arrange the basic knots in the gene network (53% of total interactions). A number of significantly different complex genotypes was revealed at patients with primary lymphedema with normal body mass index (BMI < 25) and obesity (BMI < 30). Hence, frequency of complex genotype VEGF +936 CC: MMP3 -1171 5А6А:MMP9 -1562 CC in the patients with obesity is increased more 5.5-fold compared to the patients with normal BMI.

The data obtained may presume a certain value of the analyzed gene polymorphisms in pathogenesis of primary lymphedema. Topological analysis of gene networks allows to study the structural and functional organization of gene-gene interactions for development of approaches to individyal preventive maintenance and therapy of the disease.

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