Ассоциация rs699947 и rs201063 гена VEGF с уровнями фактора роста эндотелия сосудов в сыворотке крови детей с люпус нефритом

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.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

Полиморфизм некоторых генов JAK-STAT сигнального пути и его регуляторов у пациентов с системной красной волчанкой и люпус нефритом в Республике Беларусь

Genes of interest – STAT4, PTPN2 and PTPN22 – are components of the JAK-STAT signaling pathway, one of the important regulators of the immune system. The JAK-STAT pathway plays a key role in the development of both systemic lupus erythematosus (SLE) and its manifestation, lupus nephritis (LN) by mediating interferon levels and promoting IFN-induced gene expression. We investigated the allele and genotypes frequencies at the polymorphic loci of the STAT4 (rs7574865, rs3821236), PTPN2 (rs2542151, rs7234029) and PTPN22 (rs2476601) genes in groups of children (n = 37) and adults (n = 63) with SLE and LN. The control group included children (n = 420) and adults (n = 345) without autoimmune diseases. The analysis of the combined group of pediatric and adult patients revealed that the rs7574865 polymorphic locus of the STAT4 gene is associated with the risk of developing SLE (Т: OR 1,99 [1,42–2,79], р = 0,0001; TT: OR 3,36 [1,64–6,87], р = 0,0018) and LN (Т: OR 1,91 [1,32–2,78], р = 0,0008; TT: OR 4,25 [2,02–8,95], р = 0,0004). These associations also persisted when analyzing the pediatric and adult groups of patients with SLE and LN separately. Moreover, the rs7574865 polymorphic locus of the STAT4 gene appears to be a common genetic risk factor for autoimmune diseases development. The association of the polymorphic locus rs2542151 of the PTPN2 gene with the SLE (G: OR 1,66 [1,12–2,47], p = 0,014; GT: OR 1,74 [1,10–2,77], р = 0,021) and LN (G: OR 1,87 [1,21–2,88], р = 0,006; GT: OR 1,90 [1,13–3,18], р = 0,017) susceptibility was also found in a combined group of patients. The polymorphic loci rs7234029 in the PTPN2 gene and rs2476601 in the PTPN22 gene were not associated with SLE or LN regardless of the age of the patients.Исследуемые гены STAT4, PTPN2 и PTPN22 являются звеньями JAK-STAT сигнального пути, одного из важных регуляторов функционирования иммунной системы. Опосредованное им повышение уровня интерферонов и экспрессии индуцируемых ими генов играет ключевую роль в развитии как системной красной волчанки (СКВ), так и ее проявления – люпус нефрита (ЛН). В работе определены частоты генотипов и аллелей в полиморфных локусах генов STAT4 (rs7574865, rs3821236), PTPN2 (rs2542151, rs7234029) и PTPN22 (rs2476601) в группах детей (n = 37) и взрослых (n = 63) с СКВ и ЛН. В контрольную группу включены дети (n = 420) и взрослые (n = 345) без аутоиммунных заболеваний. Анализ объединенной группы пациентов детского и взрослого возраста позволил установить, что полиморфный локус rs7574865 гена STAT4 является маркером риска развития СКВ (Т: OR 1,99 [1,42–2,79], р = 0,0001; TT: OR 3,36 [1,64–6,87], р = 0,0018) и ЛН (Т: OR 1,91 [1,32–2,78], р = 0,0008; TT: OR 4,25 [2,02–8,95], р = 0,0004). Эти ассоциации сохранялись и при анализе детской и взрослой групп пациентов с СКВ и ЛН по отдельности. При этом полиморфный локус rs7574865 гена STAT4 является, по-видимому, общим генетическим фактором риска возникновения аутоиммунных заболеваний. Также выявлена ассоциация полиморфного локуса rs2542151 гена PTPN2 с риском развития СКВ (G: OR 1,66 [1,12–2,47], p = 0,014; GT: OR 1,74 [1,10–2,77], р = 0,021) и ЛН (G: OR 1,87 [1,21–2,88], р = 0,006; GT: OR 1,90 [1,13–3,18], р = 0,017) в объединенной группе пациентов. Полиморфные локусы rs7234029 гена PTPN2 и rs2476601 гена PTPN22 не были ассоциированы с СКВ или ЛН вне зависимости от возраста пациентов

Immunoglobulin A nephropathy in children: a review of the literature and own data

Background. Immunoglobulin A (IgA) nephropathy is the most common primary chronic glomerulopathy in adults and children. It is believed that in childhood it has a benign course, but in adults it ranks first among all glomerulopathies as a cause of end-stage renal disease at a young age. The purpose of the study was analysis of literature data, clinical, immunopathological and morphological changes in IgA nephropathy to identify children at high risk of disease progression. Materials and methods. The study included 53 patients with IgA nephropathy (36 boys, 17 girls) aged from 6 to 17 years, who were under observation at the Republican Center for Pediatric Nephrology and Renal Replacement Therapy in Minsk. Inclusion criteria: predominance of dominant/co-dominant mesangial IgA deposits in kidney specimen according to MEST-C 2016 classification. The duration of follow-up ranged from 13 months to 6 years. Results. In children with IgA nephropathy, the concentration of aberrant deGal-IgA1 was significantly higher as compared to the patients with Henoch-Schonlein nephritis and healthy individuals (p < 0.001). The risk of rapid progression and onset of end-stage renal disease is inc reased in patients with hypertension, proteinuria over 0.5 g/day, a decrease in estimated glomerular filtration rate less than 60 ml/min, the presence of segmental sclerosis, tubular atrophy, interstitial fibrosis, fibrous and fibrocellular crescents, a large number of IgA deposits in combination with C3 in the biopsy specimen. Conclusions. In childhood in most cases, IgA nephropathy has a low rate of progression and does not lead to a complete loss of kidney function

Evaluation of the contribution of herpes virus infection to the development and progression of chronic glomerular diseases in children

Background. Etiology of chronic glomerular diseases is not completely known to the present day. A number of factors, including viral infections, are described. Aim of the study: determination of antibodies to Epstein-Barr virus (EBV) (immunoglobulin (Ig) G to the nuclear and early antigen (AG), IgG and IgM to viral capsid AG), cytomegalovirus (CMV) (IgG, IgM), herpes simplex virus (HSV) (IgM, IgG), specific DNA fragments of herpes and polyomaviruses (BK and JC) in the blood serum and kidney tissue to clarify the role of viral infection in the development of glomerulopathies (GP) in children. Materials and methods. One hundred thirty children with primary and secondary GP were examined for the presence of antibodies and DNA fragments of herpes and polyomaviruses, including 42 recipients of the kidney transplant (Tx); 36 appa­rently healthy individuals were included in the control group. Ultrastructural analysis of kidney tissue for herpes viruses was performed. Results. IgM to HSV and IgM to CMV were detected in the sera of patients with secondary and primary GP more often than in controls (17.1 and 12.8 % vs. 0, 20 and 17 % vs. 5.5 %, respectively), and also children with Tx (vs. 0 % for HSV, 5 % for CMV, and 7 % for EBV, respectively). In 5 cases of secondary GP, IgM to 2 or more herpes viruses simultaneously were detected. In the blood serum of 24.4 % of children with secondary GP, both antibodies to EBV (IgG to early AG and IgM to viral capsid AG) and nucleic acids of HSV, CMV and EBV were detected. The ultrastructural analysis of 10 biopsy specimens showed the presence of type 1 and 2 HSV DNA in one case and CMV DNA in 2 cases. The features of the course of GP associated with herpetic infection are presented. Conclusions. Herpes viruses influence the development and course of the pathological process in chronic GP. The presented algorithm of virological examination of children with GP can be used in the practice of a nephrologist