Кирилл Савостьянов - Academia.edu (original) (raw)

Papers by Кирилл Савостьянов

Diabetes-metabolism Research and Reviews, May 1, 2004

Background Oxidative stress is involved in the origin of type 1 diabetes. Low efficiency of the s... more Background Oxidative stress is involved in the origin of type 1 diabetes. Low efficiency of the scavenging antioxidant system has been shown to be related to the pathogenesis of the disease. This, therefore suggests that genes encoding catalase and other antioxidant enzymes may implicate in the development of type 1 diabetes. Methods Nine microsatellite markers that cover about 10 megabases around the catalase (CAT) gene on chromosome 11p13 were analyzed using polymerase chain reaction (PCR) and fluorescence-based genotyping on an automatic DNA sequencer. We also evaluated three single-nucleotide polymorphisms (SNP) within genes encoding catalase (T1667T and C(−262)T dimorphism) and ETS homologous factor (EHF) (C255T SNP) using a PCR-restriction fragment-length polymorphism approach. Multipont linkage analysis in 37 affected sibling pairs was performed using GENEHUNTER 2.1. We examined the markers for association with the disease by transmission disequilibrium tests in 57 discordant sibling pairs and by a case-control study in 258 unrelated healthy donors and 247 affected patients. Results We obtained close-to-suggestive evidence of linkage to type I diabetes, with the maximum linkage peak between markers D11S907 and D11S2008. Analysis of three SNPs at the CAT and EHF gene located within the region of maximum linkage showed that T1667T and C(−262)T markers of the CAT gene are strongly associated with the disease. Conclusion Our findings support evidence of a new putative type 1 diabetes susceptibility locus on chromosome 11p13 and suggest that the CAT gene may play a role in conferring susceptibility to the disorder in Russian patients.

Annals of the Rheumatic Diseases, Jun 1, 2014

Results: 56 patients with polyarticular form of JIA, fulfilling the ILAR criteria, persisting at ... more Results: 56 patients with polyarticular form of JIA, fulfilling the ILAR criteria, persisting at adulthood were included with mean age of 25±8.1 years and mean disease duration of 14.3±8.7 years. Antibodies status (anti-CCP, RF and AAN) was performed after a mean of 11.6±9 years after the diagnosis. 29/56 (52%) patients were anti-CCP positive. Anti-CCP positive pJIA had a significant association with presence of RF (97% vs 26%, p<0.0001), a higher use of biotherapies (86% vs 70%, p=0.02, OR=4.3 [1.2-15.8]) and were older at diagnosis (13±3.4 vs 7.6±4.9, p=0.00001) than anti-CCP negative patients. No differences have detected for sex, presence of antinuclear antibodies, synovitis, CRP, Corticosteroids, DMARDs and surgery. Radiographic damages were similar between the two subgroups for erosion (16.2±21.3 vs 14.8±28.3), joint space narrowing (24.3±29.3 vs 23.8±34.9) and total scores (40.4±46.8 vs 38.7±61.8). In the subgroup of RF positive pJIA (n=35), 28 were anti-CCP positive and 7 negative. No differences for sex, clinical data, medical treatments, surgery and radiographic damages have been detected. Conclusions: In this large cohort of polyarticular JIA patients at adulthood, anti-CCP antibodies are associated with a higher need of biotherapies but not with a more structural radiographic severe disease. A small subgroup of patients were RF+ and anti-CCP-. Comparison of RF+ and anti-CCP+ and RF+ and anti-CCPpatients showed that anti-CCP did not seem to bring more information as RF but a larger cohort will be necessary to confirm these results. Finally, our results suggest that polyarticular JIA patients evolving at adulthood are independent of anti-CCP antibodies status at the difference of the pJIA in childhood in which anti-CCP status remains a poor prognostic factor.

Diabetes Research and Clinical Practice, Sep 1, 2000

Molecular Biology, Mar 1, 2004

The allele and genotype frequency distributions of polymorphic markers of genes coding for antiox... more The allele and genotype frequency distributions of polymorphic markers of genes coding for antioxidant enzymes were compared for type 1 diabetes mellitus patients with or without diabetic polyneuropathy (DPN). The groups (total 180 patients) had nonoverlapping (polar) phenotypes. Group DPN+ included 86 patients with DPN and diabetic record no more than 5 years. Control group DPN-included patients without DPN and diabetic record of at least 10 years. Comparative analysis with Fisher's exact test revealed a significant difference in allele and genotype frequency distributions of the í(-262)ë polymorphic marker of the CAT gene. Polymorphic markers C1167T of the CAT gene, Pro/Leu of the GPX1 gene, 0/+ of the GSTT1 gene, and 0/+ of the GSTM1 gene showed no significant difference in allele or genotype frequency distribution. On this evidence, these markers were not associated with DPN in the sample examined.

Journal of Cystic Fibrosis, Jun 1, 2023

Vestnik Rossiĭskoĭ akademii meditsinskikh nauk / Rossiĭskaia akademiia meditsinskikh nauk, 2014

We represented a case history of multiple hepatic adenomas in an adolescent with severe clinical ... more We represented a case history of multiple hepatic adenomas in an adolescent with severe clinical course of glycogen storage disease type 1b (compound heterozygous mutations с.1042_1043delCT and с.817G>A in the SLC37A4). The patient was prescribed a raw cornstarch and hepatoprotectors therapy, but he and his parents had low compliance to treatment. At the age of 13,5 years ultrasound investigation and computed tomography revealed multiple adenomas. Due to the severe condition of the patient it was impossible to perform focal hepatic biopsy. At present time the patient receives treatment focused on correction of metabolic disturbances, thereafter an applicability of exploratory puncture will be settled for the further patient surveillance. The modern data on causes and risk factors of hepatic adenomas in such patients, the possibility of their malignization, the algorithm of the follow-up and the methods of treatment are presented in the discussion.

Nervno-myšečnye bolezni, Mar 29, 2016

Болезнь Помпе (БП)-редкое, прогрессирующее, часто фатальное наследственное аутосомно-рецессивное ... more Болезнь Помпе (БП)-редкое, прогрессирующее, часто фатальное наследственное аутосомно-рецессивное заболевание, диагностика которого затруднена высокой гетерогенностью клинических проявлений и низкой осведомленностью врачей. Доступность лабораторной диагностики редких болезней растет с каждым годом, и БП не является исключением. Лаборатории России и мира за последние несколько лет достигли значительных успехов в ускорении и увеличении точности диагностики БП. К сожалению, в русскоязычной литературе недостаточно актуальной информации о лабораторной диагностике БП. Данный обзор призван заполнить этот пробел.

Human Immunology, Nov 1, 2010

Melanoma differentiation-associated 5 (MDA5), a product of the IFIH1 gene, is responsible for sen... more Melanoma differentiation-associated 5 (MDA5), a product of the IFIH1 gene, is responsible for sensing double-stranded viral double-stranded RNA (RNA). In this study, we showed a significant association of two rare IFIH1 variants, rs35744605 (E627X) and rs35667974 (I923V), with decreased risk of type 1 diabetes (T1D) in a Russian population (for the allele X627, odds ratio [OR] ϭ 0.39, 95% confidence interval [95% CI] ϭ 0.22-0.69, p ϭ 0.0015; for the allele V923, OR ϭ 0.45, 95% CI, 0.30-0.66, p ϭ 5.4 ϫ 10 Ϫ5). We detected a 3.5-fold greater frequency of enteroviral RNA in T1D subjects compared with controls (p Ͻ1.0 ϫ 10 Ϫ8), and 2.1-fold more frequent presence of viral RNA in T1D patients with a recent-onset diabetes (duration Յ1 year) compared with those with a longer disease (p Ͻ1.0 ϫ 10 Ϫ8). The carriage of the predisposing IFIH1 EI/EI haplogenotype was significantly associated with a 1.5-to 1.7-fold increase in the poly(I:C)-stimulated secretion of IFN-␤ in PMBCs compared with the other IFIH1 variants. The upregulated MDA5-dependent production of inflammatory cytokines could enhance the autoimmune destruction of ␤-cells mediated by self-reactive T-cells.

Molecular Genetics and Metabolism, Jul 1, 2000

Graves disease is complex autoimmune thyrotoxicosis. A number of genes may contribute to the deve... more Graves disease is complex autoimmune thyrotoxicosis. A number of genes may contribute to the development of the disorder. Some of them may be genes that encode cytotoxic T-lymphocyte-associated serine esterase-4 (CTLA4), subunit 2 of large multifunctional protease (LMP2), thyroid-stimulating hormone receptor (TSHR), and interleukin 1 receptor antagonist (IL1RN). We studied polymorphism of Ala17Thr CTLA4, H60R LMP2, Pro52Thr TSHR, and IL1RN-VNTR in healthy controls (n ‫؍‬ 93) and patients with Graves disease (n ‫؍‬ 78) using PCR. To study CTLA4, H60R, and TSHR polymorphism, PCR products were digested with MboI, Hin6I and PsyI, respectively. Comparative analysis using 2 test showed significant differences in allele and genotype frequency of Ala17Thr polymorphic marker between the two groups studied. Thus, the CTLA4 gene may be involved in the pathogenesis of Graves disease in a Moscow population.

Autoimmunity, 2005

Type 1 diabetes (T1D) is a multifactorial autoimmune disease, with strong genetic component. Seve... more Type 1 diabetes (T1D) is a multifactorial autoimmune disease, with strong genetic component. Several susceptibility loci contribute to genetic predisposition to T1D. One of these loci have been mapped to chromosome 1q42 in UK and US joined affected family data sets but needs to be replicated in other populations. In this study, we evaluated sixteen microsatellites located on 1q42 for linkage with T1D in 97 Russian affected sibling pairs. A 2.7-cm region of suggestive linkage to T1D between markers D1S1644 and D1S225 was found by multipoint linkage analysis. The peak of linkage was shown for D1S2847 (P = 0.0005). Transmission disequilibrium test showed significant undertransmission of the 156-bp allele of D1S2847 from parents to diabetic children (28 transmissions vs. 68 nontransmissions, P = 0.043) in Russian affected families. A preferential transmission from parents to diabetic offspring was also shown for the T(-25) and T1362 alleles of the C/T(-25) and C/T1362 dimorphisms, both located at the TAF5L gene, which is situated 103 kb from D1S2847. Together with the A/C744 TAF5L SNP, these markers share common T(-25)/A744/T1362 and C(-25)/C744/T1362 haplotypes associated with higher and lower risk of diabetes (Odds Ratio = 2.15 and 0.62, respectively). Our results suggest that the TAF5L gene, encoding TAF5L-like RNA polymerase II p300/CBP associated factor (PCAF)-associated factor, could represent the susceptibility gene for T1D on chromosome 1q42 in Russian affected patients.

Autoimmunity, Feb 20, 2014

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease in children.... more Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatologic disease in children. JIA is a group of disorders that share the clinical manifestation of chronic joint inflammation. The human leukocyte antigen region (HLA) seems to be a major susceptibility locus for JIA that is estimated to account for 17% of familial segregation of the disease. To date, around 20 non-HLA loci conferring susceptibility to JIA were found. At least a half of those are shared between JIA and rheumatoid arthritis (RA), an adult rheumatic disease, thereby suggesting for similarity of pathogenic mechanisms of both diseases. New findings also suggest for a likely role of epigenetic alterations in the pathogenesis of JIA that should be investigated in the future.

Diabetes mellitus, Mar 15, 2002

Nephron, 2019

Aim: To evaluate the prevalence and clinical features of Fabry disease in patients with end-stage... more Aim: To evaluate the prevalence and clinical features of Fabry disease in patients with end-stage renal disease (ESRD) undergoing chronic hemodialysis. Methods: α-Galactosidase A activity was measured in the dried blood spots by tandem mass spectrometry in 5,572 dialysis patients (63.7% males). Diagnosis of Fabry disease was confirmed by sequencing of the GLA gene and by evaluating the globotriaosylsphingosine level in the dried blood spots. Results: Fabry disease was diagnosed in 20 (0.36%) patients at the median age of 43 years (28; 58). There were 19 males and 1 female. The prevalence of Fabry disease in dialysis patients was 0.53% in males and 0.05% in females. However, it was higher in males aged 30-49 years. Seventeen different GLA mutations were identified; 5 of them were novel. The median age at the initiation of hemodialysis was similar between patients with missense and nonsense mutations. Sixteen patients (80.0%) presented with typical symptoms of Fabry disease from childhood (neuropathic pain in 16, angiokeratoma in 7 and hypohidrosis/anhidrosis in 16). All patients had left ventricular hypertrophy, and 8 patients (40%) had a history of ischemic stroke. Two patients died (recurrent stroke in one and sudden cardiac death in another patient). Conclusions: Screening in at-risk patients remains the feasible approach to diagnose Fabry disease in patients with ESRD and their family members, given a low awareness of Fabry disease among the Russian nephrologists.

Annals of the Rheumatic Diseases, May 19, 2021

Background: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic-o... more Background: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic-onset juvenile idiopathic arthritis (sJIA) characterized by fever, hepatosplenomegaly, lymphadenopathy, coagulopathy, and rapid development of multiple organ failure. MAS is triggered by viral and bacterial infections, most often Epstein-Barr viruses, cytomegalovirus, influenza and parainfluenza viruses, parvavirus B19, yersiniosis, salmonellosis, sepsis. Despite modern diagnostic and treatment technologies, MAS still remains a formidable complication of sJIA, it is characterized by an aggressive course, a heterogeneous clinical presentation, especially in conditions of treatment with genetically engineered biological drugs, an ambiguous response to pathogenetic therapy and is accompanied by mortality in 5-10% of patients. Objectives: To analyze the clinical and laboratory features of MAS in children with sJIA and to study the genetic predisposition of this syndrome. Methods: The study included 24 patients with MAS who are being followed up in the rheumatology department of the National Medical Research Center of Children's Health, Moscow. The clinical presentation and laboratory manifestations were assessed in 24, and genetic features were described in 7 patients using a new generation sequencing with further biostatistical processing of the obtained genetic data. Results: Of 24 patients, 23 (98%) had fever, 16 (68%) patients had rash, 17 (72%)-organomegaly, 4 (16%)-polyserositis, 2 (7%)-myalgia and myopathy. All 24 (100%) patients had an increase in ferritin level of more than 684 ng/ ml, 98% of them had a high level of lactate dehydrogenase (LDH) and 97%-a high level of triglycerides. In CBC, cytopenia was found in 80% of children: in 54%-erythrocytopenia, in 74%-leukopenia, in 88%-thrombocytopenia, in 15%-sharp decrease in erythrocyte sedimentation rate. In a coagulogram of 24 patients, 90% had an increase in D-dimer, 85% had a decrease in fibrinogen. Hyponatremia presented in 95% of patients. Thus, 85% of patients met the diagnostic criteria of the HLH-2004 protocol, adapted for children with sJIA. Genetic characteristics were analyzed in 7 children out of 94 patients with MAS. They are presented in Table 1. These patients have rare and frequent variants, as well as genes polymorphisms that are associated with macrophage activation syndrome.

Journal of Investigative Dermatology, Sep 1, 2019

Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare monogenic skin disease characterized by the... more Brooke-Spiegler syndrome (BSS; OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis gene (CYLD). Concerning the so far reported phenotypes and the underlying CYLD mutations, it is difficult to establish genotype-phenotype correlations in BSS. We have recently investigated a Hungarian family (with Bukovinian origin) and an Anglo-Saxon BSS pedigree, in whom the affected family members-despite of carrying the same diseasecausing mutation (c.2806C>T, p.Arg936X) of the CYLD gene-show striking differences in their phenotypes. The aim of our study was to identify phenotype modifier genetic factors, which could help the understanding of genotype-phenotype correlations in BSS. Comparing the WES data of the Hungarian and Anglo-Saxon BSS patients, here we have identified three putative phenotype modifying genetic variants: the rs1053023 SNP of the signal transducer and activator of transcription 3 (STAT3) gene, the rs1131877 SNP of the tumor necrosis factor receptor-associated factor 3 (TRAF3) gene and the rs202122812 SNP of the neighbor of BRCA1 gene 1 (NBR1) gene. Our study contributes to the accumulating evidence describing the clinical importance of genetic phenotype modifying factors, which have high potential in the elucidation of genotype-phenotype correlations and disease prognosis.

Nevrologičeskij žurnal imeni L.O. Badalâna, Jan 15, 2023

Nervous Developmental Disorder with Involuntary Movements (NEDIM) (OMIM 617493) is a rare movemen... more Nervous Developmental Disorder with Involuntary Movements (NEDIM) (OMIM 617493) is a rare movement disorder in children on the spectrum of GNAO1-associated movement disorders. With NEDIM, movement disorders appear in early childhood, progress and lead to disability. The disease is caused by pathogenic heterozygous variants in the GNAO1 gene and has an autosomal dominant mode of inheritance. The epidemiology of NEDIM has not yet been established. Clinical symptoms are extensive, ranging from severe motor and cognitive impairment with self-injurious behaviour and seizures to a mild phenotype of movement disorders without mental retardation and seizures. Some patients develop epilepsy. Hyperkinetic syndrome in most children is manifested with chorea, athetosis, dystonia, and ballism, affecting the muscles of the body, limbs and face. According to MRI, in some patients, gradually progressive atrophy of the brain substance is visualized. Currently, the disease has no developed pathogenetic methods of therapy. Treatment is symptomatic, including various drug regimens to reduce the severity of movement disorders and seizures. Management of nutrition of the patient and the prevention of secondary complications of movement disorders are also important. In foreign sources there is described the experience of using topiramate and teterabenazine, as well as deep brain stimulation (DBS), which demonstrate a good effect in the form of a significant reduction in the frequency of dystonic storms and the severity of motor disorders. The article presents a clinical case of diagnosis and treatment of a child with this disease, and also current trends in therapy.

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PubMed, Jun 15, 2005

Early studies of the association of a large group of gene candidates indicated that only the poly... more Early studies of the association of a large group of gene candidates indicated that only the polymorphic markers of angiotensin-converting enzyme (ACE) I gene and endothelial vascular cell NO-synthetase (NOS3) gene were associated with diabetic nephropathy (DN) in type 1 diabetes mellitus. The purpose of this study was to examine DN predisposition in patients with type 1 DM, by using the polymorphic markers of the genes of apolipoproteins Е (АРОЕ) and В (АРОВ) which encode for lipid metabolic proteins, as well as polymorphic microsatellites in the chromosomal region 3q21-q25. Two groups of patients of patients with type 1 DM with (n = 54) and without (n = 65) DN were examined to analyze the gene association with DN. Analyzing the frequencies of the alleles and genotypes of the polymorphic marker E2/E3/E4 ofAPOR gene has indicated that the carriers of the allele E3 and the genotype E3/ E3 have a higher risk for DN (OR = 2.08 and 2.16, respectively). In case of АРОВ gene, the carriers of allele I and genotype II of the polymorphic marker I/D have been ascertained to have a higher risk for DN (OR = 1.91 and 2.11, respectively) while those of allele Dhave, on the contrary, a lower risk for DN (OR = 0.52). The authors have revealed an association of a group of polymorphic microsatellites with DN in the chromosomal region 3q21-q25. There is the greatest association for the marker D31550. The carriers of allele 12 (OR = 4.85) and genotype 12/14 (OR = 6.25) have a much higher risk for DN. In all probability, in the chromosomal region 3q21-q25, there is a major gene that initiates the development of DN whereas other genes associated with DN affect the rate of its progression to a greater extent. Thus, among the Moscow Russian dwellers suffering from type 1 DM, the progression of DN is mainly associated with the genes of ACE, NOS3, APOE, and АРОВ while the major gene that determines the first stages of DN development in type 1 DM is likely to be located in the chromosomal region 3q21-q25.

Problemy e̊ndokrinologii, Jun 15, 2001

Distribution of alleles and genotypes of microsatellite D6S392 neighboring mitochondrial superoxi... more Distribution of alleles and genotypes of microsatellite D6S392 neighboring mitochondrial superoxide dismutase (SOD2) gene and of two polymorphous markers (minisatellite ecNOS4a/4b and mutation in codone 298: replacement of glutamic acid (Glu) with asparaginic (Asp) acid) was studied in patients with insulin dependent diabetes mellitus (IDDM) with and without diabetic nephropathy (DN) (36 and 56 patients, respectively). Distribution of locus D6S392 alleles and polymorphous marker Glu298Asp was virtually the same in both groups. Differences were observed for minisatellite ecNOS4a/4b. In DN patients the content of allele 4a and of genotype 4a/4b is increased in comparison with patients without DN (38.9 vs. 22.3%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.02, and 61.1 vs. 41.7%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05, respectively). Decrease in the percent age of 4b/4b genotype and allele 4b in DN patients are also significant (30.6 vs. 57.1%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.02, and 61.1 vs. 77.1%, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.02). Hence, polymorphous site ecNOS4b/4a of NOS3 gene is associated with DN development in patients with IDDM living in Moscow.

Russian Journal of Genetics, Feb 1, 2007

A comparative analysis of allele and genotype distribution of polymorphic markers Val762Ala and L... more A comparative analysis of allele and genotype distribution of polymorphic markers Val762Ala and Leu54Phe of ADPRT1 gene encoding poly(ADP-ribose)polymerase1 has been performed in chronic glomerulonephritis patients compared to normal controls. This has shown a significant difference in the ADPRT1 gene polymorphic marker Val762Ala allele and genotype frequency distribution between chronic glomerulonephritis patients and healthy controls (according to Fisher's exact test). At the same time the allele and genotype frequency for a polymorphic marker Leu54Phe distribution did not show significant difference between these groups. Therefore, we have concluded that the ADPRT1 gene polymorphic marker Val762Ala is associated with the development of chronic glomerulonephritis in Russian patients of the Moscow region.

Diabetes mellitus, Sep 15, 2000