danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1561-8323-2022-66-6-614-621dan-1101Research ArticleМЕДИЦИНАMEDICINEАссоциация rs699947 и rs201063 гена VEGF с уровнями фактора роста эндотелия сосудов в сыворотке крови детей с люпус нефритомAssociation of VEGF gene rs699947 and rs2010963 polymorphisms with vascular endothelial growth factor levels in the blood serum of children with lupus nephritisНикитченкоН. В.NikitchenkoN. N.

Никитченко Наталья Васильевна – научный сотрудник.

ул. Академическая, 27, 220072, Минск

Natallia V. Nikitchenko – Researcher, Institute of Genetics and Cytology of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk

N.Nikitchenko@igc.byКозыроИ. А.KazyraI. A.

Козыро Инна Александровна – доктор медицинских наук, доцент.

пр. Дзержинского, 83, 220116, Минск

Ina A. Kazyra – D. Sc. (Medicine), Associate Professor, Belarusian State Medical University.

83, Dzerzhinski Ave., 220116, Minsk

kozyroia@mail.ruБелькевичА. Г.BialkevichH. G.

Белькевич Анна Геннадьевна – кандидат медицинских наук, ассистент.

пр. Дзержинского, 83, 220116, Минск

Hanna G. Bialkevich – Ph. D. (Medicine), Assistant, Belarusian  State  Medical  University.

83,  Dzerzhinski  Ave., 220116, Minsk

belka99@mail.ruСукалоА. В.SukaloA. V.

Сукало Александр Васильевич – академик, доктор медицинских наук, профессор.

пр. Дзержинского, 83, 220116, Минск

Alexandr V. Sukalo – Academician, D. Sc. (Medicine), Professor.

83, Dzerzhinski Ave., 220116, Minsk

ГончароваР. И.GoncharovaR. I.

Гончарова Роза Иосифовна – доктор биологических наук, профессор, главный научный сотрудник.

ул. Академическая, 27, 220072, Минск

Roza I. Goncharova – D. Sc. (Biology), Professor, Chief Researcher, Institute of Genetics and Cytology of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk

R.Goncharova@igc.byИнститут генетики и цитологии Национальной академии наук БеларусиInstitute of Genetics and Cytology of the National Academy of Sciences of BelarusБелорусский государственный медицинский университетBelarusian State Medical University202203012023666614621Copyright © Никитченко Н.В., Козыро И.А., Белькевич А.Г., Сукало А.В., Гончарова Р.И., 20232023Никитченко Н.В., Козыро И.А., Белькевич А.Г., Сукало А.В., Гончарова Р.И.Nikitchenko N.N., Kazyra I.A., Bialkevich H.G., Sukalo A.V., Goncharova R.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/1101

Гены ростовых факторов VEGF и TGFB1 задействованы в нормальном функционировании почек, а некоторые полиморфные локусы этих генов обуславливают генетическую предрасположенность к возникновению аутоиммунных заболеваний, в том числе к системной красной волчанке (СКВ) и ее опасному осложнению – люпус нефриту (ЛН). Продукты данных генов, в частности, протеин фактора роста эндотелия сосудов и протеин трансформирующего фактора роста β1 используются в клинической практике в качестве маркеров эндотелиальной дисфункции для ранней диагностики патологии почек. Однако связь экспрессии этих протеинов с генотипами/ аллелями полиморфных локусов вышеуказанных генов изучена недостаточно. В работе был проведен анализ ассоциаций генотипов генов TGFB1 (rs1800469) и VEGF (rs699947 и rs2010963) с концентрацией их продуктов в сыворотке крови детей Беларуси с ЛН в период обострения и ремиссии заболевания. Установлена ассоциация между полиморфными  вариантами  rs699947  и  rs2010963  гена  VEGF  и  концентрацией  продукта  гена  в  сыворотке  крови у педиатрических пациентов с ЛН в период обострения. Выявлено, что гомозиготный минорный генотип AA полиморфного локуса rs699947 и группа генотипов GC + СС, содержащих не менее одного минорного аллеля локуса rs2010963, ассоциированы с более высоким уровнем продукта гена в сыворотке крови детей с ЛН в период обострения заболевания (р < 0,001 и р = 0,036 соответственно). В исследовании не обнаружено достоверной связи между полиморфными вариантами гена TGFB1 (rs1800469) и содержанием его продукта в сыворотке крови. Таким образом, полиморфные варианты VEGF, ассоциированные с повышенной концентрацией продукта гена в крови при обострении заболевания, могут рассматриваться как маркеры риска обострения заболевания у пациентов с ЛН.

The growth factor genes VEGF and TGFB1 are involved in the normal functioning of the kidneys, and some polymorphic loci of these genes determine a genetic predisposition to the autoimmune diseases, including systemic lupus erythematosus (SLE) and its dangerous complication, lupus nephritis (LN). The products of these genes, in particular, the vascular endothelial growth factor protein and the transforming growth factor β1 protein are used in clinical practice as markers of endothelial dysfunction for early diagnosis of kidney pathology. However, the relationship between the expression of these proteins and the genotypes/alleles of the polymorphic loci of these genes has not been studied enough, which requires clarification of this issue for the child population of Belarus. In this work, we analyzed the associations of the TGFB1 (rs1800469) and VEGF (rs699947 and rs2010963) gene genotypes with the concentration of their products in the blood serum of patients with LN during exacerbation and remission of the disease. The study did not find a significant relationship between polymorphic variants of the TGFB1 gene (rs1800469) and levels of its product in the blood. An association has been established between the rs699947 and rs2010963 polymorphic variants of the VEGF gene and the serum concentration of the gene product in pediatric patients with LN during exacerbation. It was found that the homozygous minor genotype AA of the polymorphic locus rs699947 and the group of genotypes GC + CC containing at least one minor allele of the locus rs2010963 are associated with higher levels of the gene product in the blood serum of children with LN during disease exacerbation (p < 0.001 and p = 0.036, respectively). Thus, VEGF polymorphic variants associated with an increased concentration of the gene product in the blood serum during disease exacerbation can be considered as markers of the risk of disease exacerbation in patients with LN.

системная красная волчанкалюпус нефритгены VEGF и TGFB1протеин фактора роста эндотелия сосудовпротеин трансформирующего фактора роста β1полиморфный локусsystemic lupus erythematosuslupus nephritisVEGF and TGFB1 genesvascular endothelial growth factor proteintransforming growth factor β1 proteinpolymorphic locusРабота выполнена в рамках задания 2.37 подпрограммы 2 «Молекулярно-генетическое изучение структурной и функциональной организации геномов растений, животных, микроорганизмов и человека как фундаментальной основы новейших геномных биотехнологий» («Структурная и функциональная геномика») ГПНИ «Биотехнологии» на 2016–2020 гг.The work was carried out within the framework of task 2.37 of Subprogram 2 “Molecular-genetic study of structural and functional organization of genomes of plants, animals, microorganisms, and humans as the fundamentals of the newest genome biotechnologies” (“Structural and functional genomics”) SPSR “Biotechnologies” for 2016–2020.ReferencesClinical features and long-term outcomes of systemic lupus erythematosus: comparative data of childhood, adult and late-onset disease in a national register / S. Sousa [et al.] // Rheumatol. Int. – 2016. – Vol. 36, N 7. – P. 955–960. https://doi.org/10.1007/s00296-016-3450-2Sousa S., Goncalves M. J., Ines L. S., Eugenio G., Jesus D., Fernandes S. [et al.]. Clinical features and long-term out-comes of systemic lupus erythematosus: comparative data of childhood, adult and late-onset disease in a national register. Rheumatology International, 2016, vol. 36, no. 7, pp. 955–960. https://doi.org/10.1007/s00296-016-3450-2Iwamoto, T. Genetics of Human Lupus Nephritis / T. Iwamoto, T. B. Niewold // Clin. Immunol. – 2017. – Vol. 185. – P. 32–39. https://doi.org/10.1016/j.clim.2016.09.012Iwamoto T., Niewold T. B. Genetics of Human Lupus Nephritis. Clinical Immunology, 2017, vol. 185, pp. 32–39. https://doi.org/10.1016/j.clim.2016.09.012An update on genetic susceptibility in lupus nephritis / K. Song [et al.] // Clin. Immunol. – 2020. – Vol. 215. – P. 108389. https://doi.org/10.1016/j.clim.2020.108389Song K., Liu L., Zhang X., Chen X. An update on genetic susceptibility in lupus nephritis. Clinical Immunology, 2020, vol. 215, pp. 108389. https://doi.org/10.1016/j.clim.2020.108389Biomarkers associating endothelial dysregulation in pediatric-onset systemic lupus erythematous / W. F. Lee [et al.] // Pediatr. Rheumatol. – 2019. – Vol. 17, N 1. – P. 69. https://doi.org/10.1186/s12969-019-0369-7Lee W. F., Wu C. Y., Yang H. Y., Lee W. I., Chen L. C., Ou L. S., Huang J. L. Biomarkers associating endothelial dysregulation in pediatric-onset systemic lupus erythematous. Pediatric Rheumatology, 2019, vol. 17, no. 1, pp. 69. https://doi.org/10.1186/s12969-019-0369-7Munroe, M. E. Genetics of Lupus Nephritis: Clinical Implications / M. E. Munroe, J. A. James // Seminars in Nephrology. – 2015. – Vol. 35, N 5. – P. 396–409. https://doi.org/10.1016/j.semnephrol.2015.08.002Munroe M. E., James J. A. Genetics of Lupus Nephritis: Clinical Implications. Seminars in Nephrology, 2015, vol. 35, no. 5, pp. 396–409. https://doi.org/10.1016/j.semnephrol.2015.08.002Hu, G. Revealing transforming growth factor-beta signaling transduction in human kidney by gene expression data mining / G. Hu, K. Jain, M. Hurle // OMICS. – 2005. – Vol. 9, N 3. – P. 266–280. https://doi.org/10.1089/omi.2005.9.266Hu G., Jain K., Hurle M. Revealing transforming growth factor-beta signaling transduction in human kidney by gene expression data mining. OMICS, 2005, vol. 9, no. 3, pp. 266–280. https://doi.org/10.1089/omi.2005.9.266Changes to signal peptide and the level of transforming growth factor-β1 due to T869C polymorphism of TGF β1 associated with lupus renal fibrosis / H. Susianti [et al.] // Springerplus. – 2014. – Vol. 3, N 1. – P. 514. https://doi.org/10.1186/2193-1801-3-514Susianti H., Handono K., Purnomo B. B., Widodo N., Gunawan A., Kalim H. Changes to signal peptide and the level of transforming growth factor-β1 due to T869C polymorphism of TGF β1 associated with lupus renal fibrosis. Springerplus, 2014, vol. 3, no. 1, pp. 514. https://doi.org/10.1186/2193-1801-3-514Meta-analysis of associations of vascular endothelial growth factor protein levels and –634G/C polymorphism with systemic lupus erythematosus susceptibility / W. Tang [et al.] // BMC Medical Genetics. – 2019. – Vol. 20. – P. 46. https://doi.org/10.1186/s12881-019-0783-1Tang W., Zhou T., Zhong Z., Zhong H. Meta-analysis of associations of vascular endothelial growth factor protein levels and –634G/C polymorphism with systemic lupus erythematosus susceptibility. BMC Medical Genetics, 2019, vol. 20, no. 1, pp. 46. https://doi.org/10.1186/s12881-019-0783-1European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative / N. Groot [et al.] // Ann. Rheum. Dis. – 2017. – Vol. 76, N 12. – P. 1965–1973. https://doi.org/10.1136/annrheumdis-2017-211898Groot N., de Graeff N., Marks S. D., Brogan P., Avcin T., Bader-Meunier B. [et al.]. European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative. Annals of the Rheumatic Diseases, 2017, vol. 76, no. 12, pp. 1965–1973. https://doi.org/10.1136/annrheumdis-2017-211898Национальный центр биотехнологической информации = National Center for Biotechnology Information NCBI, dbSNP [Электронный ресурс]. – Режим доступа: https://www.ncbi.nlm.nih.gov/snp/rs699947#frequency_tab. – Дата доступа: 10.06.2019.National Center for Biotechnology Information NCBI, dbSNP. Available at: https://www.ncbi.nlm.nih.gov/snp/rs699947#frequency_tab (accessed 10 June 2019).Investigate correlated alleles for a pair of variants in high LD [Electronic resource]. – Mode of access: https://ldlink. nci.nih.gov/. – Date of access: 10.06.2019.Investigate correlated alleles for a pair of variants in high LD. Available at: https://ldlink.nci.nih.gov/ (accessed 10 June 2019).IL-6 and TGF-β gene polymorphisms, their serum levels, as well as HLA profile, in patients with systemic lupus erythematosus / A. Paradowska-Gorycka [et al.] // Clin. Exp. Rheumatol. – 2019. – Vol. 37, N 6. – P. 963–975.Paradowska-Gorycka A., Roszak M., Stypinska B. [et al.]. IL-6 and TGF-β gene polymorphisms, their serum levels, as well as HLA profile, in patients with systemic lupus erythematosus. Clinical and Experimental Rheumatology, 2019, vol. 37, no. 6, pp. 963–975.Genetic risk factors in lupus nephritis and IgA nephropathy – no support of an overlap / M. T. Vuong [et al.] // PLoS One. – 2010. – Vol. 5, N 5. – Art. e10559. https://doi.org/10.1371/journal.pone.0010559Vuong M. T., Gunnarsson I., Lundberg S., Svenungsson E., Wramner L., Fernström A., Syvänen A.-C., Do L. T., Jacobson S. H., Padyukov L. Genetic risk factors in lupus nephritis and IgA nephropathy – no support of an overlap. PLoS One, 2010, vol. 5, no. 5, art. e10559. https://doi.org/10.1371/journal.pone.0010559Single nucleotide polymorphism T869C of transforming growth factor-beta 1 gene and systemic lupus erythematosus: association with disease susceptibility and lupus nephritis / S. K. Sayed [et al.] // Egypt. J. Immunol. – 2014. – Vol. 21, N 2. – P. 9–21.Sayed S. K., Galal S. H., Herdan O. M., Mahran A. M. Single nucleotide polymorphism T869C of transforming growth factor-beta 1 gene and systemic lupus erythematosus: association with disease susceptibility and lupus nephritis. Egyptian Journal of Immunology, 2014, vol. 21, no. 2, pp. 9–21.Lack of association between interleukin-10, transforming growth factor-beta gene polymorphisms and juvenile-onset systemic lupus erythematosus / A. Rezaei [et al.] // Clin. Rheumatol. – 2015. – Vol. 34, N 6. – P. 1059–1064. https://doi.org/10.1007/s10067-015-2877-2Rezaei A., Ziaee V., Sharabian F. T., Harsini S., Mahmoudi M., Soltani S., Sadr M., Moradinejad M. H., Aghighi Y., Rezaei N. Lack of association between interleukin-10, transforming growth factor-beta gene polymorphisms and juvenile-onset systemic lupus erythematosus. Clinical Rheumatology, 2015, vol. 34, no. 6, pp. 1059–1064. https://doi.org/10.1007/s10067-015-2877-2NO-synthase inductible-2 (NOS2) and vascular endothelial growth factor (VEGF) polymorphisms in systemic lupus erythematosus among algerian patients / M. Benidir [et al.] // Lupus Science & Medicine. – 2019. – Vol. 6, N 1. – Art. A87. https://doi.org/10.1136/lupus-2019-lsm.119Benidir M., Salah S. S., Benrebha N., Djennane M., Djoudi H., Amroun H., Tamouza R., Attal N. NO-synthase inductible-2 (NOS2) and vascular endothelial growth factor (VEGF) polymorphisms in systemic lupus erythematosus among algerian patients. Lupus Science & Medicine, 2019, vol. 6, no. 1, art. A87. https://doi.org/10.1136/lupus-2019-lsm.119

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