Six novel mutations in the GCK gene in MODY patients.
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Czech Republic↗
Biomedical subjects
P Novota
Publications and source records attributed to P Novota.
Association of MHC class I chain related gene-A microsatellite polymorphism with the susceptibility to T1DM and LADA in Czech adult patients.
The results in this study suggest that microsatellite polymorphism within the transmembrane region of MIC-A gene is associated with genetic susceptibility to adult-onset of type 1 diabetes mellitus (T1DM), MIC-A5.1 allele, corrected P = 0.001, whereas it is not associated with latent autoimmune diabetes in adults (LADA) in Czech population. According to our findings, we can hypothesize that adult-onset T1DM and LADA may have partly different immunogenetic aetiopathogenesis.
Adult↗
Fluorescence-based automated fragment analysis of microsatellite polymorphism within the transmembrane region of the MIC-A gene.
MHC class I chain-related genes (MIC) are located within the MHC class I region of chromosome 6. Sequence analysis of the MIC-A gene showed a trinucleotide repeat (GCT) microsatellite polymorphism within the transmembrane region. So far, six alleles of the exon 5 of the MIC-A gene, which consist of 4, 5, 6, 9 and 10 repetitions of GCT, or five repetitions of GCT with an additional nucleotide insertion (GGCT), have been identified. Recent works support the findings that MIC-A is associated with several autoimmune diseases. In our work we present a modification of a method used for microsatellite polymorphism detection within the transmembrane region of the MIC-A gene. It is the ALFexpress fluorescence-based automated fragment analysis. We also present the frequencies of MIC-A exon 5 alleles found in the Czech population. We have identified five alleles of the transmembrane region of MIC-A, which comprise 4, 5, 6 and 9 repetitions or five repetitions with an additional nucleotide insertion. The most frequent allele was A5.1 (59.3%) and the less frequent was the allele A5 (20.0%). No A7, A8 or A10 alleles were identified.
Czech Republic↗
The frequency of alleles of the Pro12Ala polymorphism in PPARgamma2 is different between healthy controls and patients with type 2 diabetes.
The aim of this initial case-control study was to determine the association between common Pro12Ala polymorphism in the PPARgamma2 gene and type 2 diabetes in the Czech Republic. Furthermore, the effect of this polymorphism on phenotypic characteristics and on levels of lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides) was studied. One hundred thirty-three patients with type 2 diabetes and 97 control subjects were investigated. PCR and RFLP analysis were used for identification of individual genotypes. In the group of patients, three samples (2.26%) were identified as homozygous for the Ala/Ala genotype and 99 samples (74.44%) were homozygotes for the Pro/Pro genotype. Thirty-one samples (23.31%) were identified as Pro12Ala heterozygous. In the control group, six samples (6.19%) were homozygous for the Ala/Ala genotype and 61 samples (62.89%) were homozygotes for the Pro/Pro genotype. Thirty samples (30.93%) were identified as Pro12Ala heterozygous. The allele frequency for the Ala allele was lower in the type 2 diabetic group than in the control group (13.91% vs. 21.43%, P = 0.022). There was no difference (at P < 0.05) between the phenotypic characteristics (BMI, sex) studied in the group of patients according to the Pro12Ala genotype. There was no significant effect of the Pro12Ala polymorphism on lipid levels.
Adult↗
[Genetic risk factors in autoimmune diabetes mellitus, their significance and function].
Autoimmune diabetes mellitus is characterized by selective destruction of beta pancreatic cells and by cellular infiltration with T- (particularly Th1) and B-lymphocytes. The marker of autoimmunity is the presence of autoantibodies (ICA, IAA, GADab, IA2ab). Etiology of the autoimmune process is still unknown. It is suggested that the pathogenesis is activated by genetic and environmental factors. Individual predisposition can influence also the onset and progression of the disease. The most important genetic risk factors of autoimmune diabetes mellitus are the HLA class II alleles (DQB1*0302, 0201; DRB1*0301, 0401; DQA1*0301, 0501) and the risk alleles of INS-VNTR of the promoter region. Recent studies have shown various genetic risk factors for the autoimmune diabetes mellitus. Individual predispositions belong to the genetic polymorphisms in cytokine genes (IL-10, IL-12, IL-18) and the microsatellite polymorphism of MHC class I chain-related gene A (MIC-A).
Autoimmunity↗
Enhancement of rat islet tolerance with bone marrow transplantation using a non-myeloablative procedure II: failure despite the presence of lymphocyte microchimerism in the fully allogeneic Lewis/Brown-Norway model.
Transplantation of donor bone marrow cells (BMTx) has been proven to be capable of including allogeneic transplant tolerance. In our previous experiments we reported the positive effect of BMTx together with short-term tacrolimus/hydrocortisone therapy on pancreatic islet survival in recipients haploidentical with donors. In this project we used the same transplant protocol to further investigate this effect in a fully mean histocompatibility system-mismatched model. Lewis male rats and Brown-Norway female rats were used as donors and recipients, respectively. Diabetic animals were treated according to four different protocols. Recipients in group I (n = 12) underwent islet transplantation (ITx) only. Group II (n = 12) and group III (n = 11) included animals treated for 52 days with tacrolimus (0.5 mg/kg) and hydrocortisone (2 mg/kg). Diabetes was induced by intravenously applied streptozocin (50 mg/kg). Seven days later islets were injected intrahepatically through the portal vein. In addition, rats in group III underwent BMTx on day 10. In group IV (n = 6) tacrolimus therapy, ITx and BMTx were used according to the previously published protocol of Ricordi et al. After more than 120 days, cumulative survival rates were 56% and 64% for recipients in groups II and III, respectively (p > 0.05). All animals in group I became hyperglycemic by day 11 following transplantation. Despite positive detection of lymphocyte microchimerism, we did not observe improved survival of allogeneic islets in animals treated with BMTx. Surprisingly, better islet survival was not found in group IV either (survival rate at 100 days: 33%). We conclude that demonstration of lymphocyte microchimerism, as detected by a sensitive polymerase chain reaction method, did not improve allogeneic islet survival in vivo and was not able to block mixed lymphocyte reaction in vitro. Whether a larger amount of transplanted hematopoietic cells could induce tolerance in this model remains to be evaluated.
Animals↗
HLA in Czech adult patients with autoimmune diabetes mellitus: comparison with Czech children with type 1 diabetes and patients with type 2 diabetes.
Type 1 diabetes results from an autoimmune insulitis, associated with HLA class II alleles. The evidence about HLA allele association is not clear in patients diagnosed after 35 years of age. In this study we have analyzed HLA alleles of DQB1 and DRB1 genes by sequence specific primer (SSP)-PCR technique in adult patients with disease onset after 35 years of age. Two hundred and eighty-one patients were divided into three groups according to the insulin therapy, the level of C peptide (CP), and GAD antibodies (anti-GAD). Group 1 (type 1 diabetes in adults) was characterized by CP less than 200 pmol/L and anti-GAD more or less than 50 ng/mL (n = 80). All of them had insulin therapy within 6 months after diagnosis. Group 2 latent autoimmune diabetes mellitus in adults (LADA) was defined by a minimum 6-month-long phase after diagnosis without insulin therapy, and was characterized by CP more than 200 pmol/L and anti-GAD more than 50 ng/mL (n = 70). Group 3 (type 2 diabetes) was characterized by CP more than 200 pmol/L and anti-GAD less than 50 ng/mL (n = 131). None ever had insulin therapy. In group 1, there was increased frequency of DRB1*04 (45.0% vs. controls 14.1%, OR = 5.0, P < 0.0005) and DQB1*0302 alleles (43.3% vs. controls 11.1%, OR = 6.1, P < 0.00005). There was increased frequency of DRB1*03 and DQB1*0201, and decreased frequency of DQB1*0602 (3.3% vs. controls 20.2%), but it was not significant. In group 2, there was a significantly increased frequency of DRB1*03 only (50.0% vs. controls 21.2%, OR = 3.7, P < 0.05). Compared with children with type 1 diabetes and adults with type 2 diabetes (group 3), we conclude that the presence of predisposing DQB1 alleles in adults with type 1 diabetes decreases with the age, probably due to environmental factors. Only the DRB1*03, but not the DQB1 gene, becomes the main predisposing allele in LADA patients. These findings suggest that the presence of HLA-DQB1*0302 identifies patients at high risk of requiring insulin treatment. Type 1 diabetes mellitus (DM) in children or adults may have partly different immunogenetic etiopathogenesis than LADA.
Adult↗
[Methods for identification of HLA antigen polymorphisms].
The HLA complex is the most polymorphic genetic system in man yet known. The variability of the HLA antigens is given by the presence of many alleles of the HLA genes. Requirements for compatibility of HLA antigens in organ and bone marrow transplantations, and also in the determination of genetic risk factors in autoimmune diseases evoke strong pressure on progress in HLA typing methods, mainly for increasing their sensitivity and resolution. For typing of the HLA antigens there are used cellular, serological, biochemical and DNA methods. For HLA class I typing there following tests are used: cytotoxic test (serological), CML (cellular), 1D--IEF (biochemical), RFLP, SSO, SSP--PCR, and SBT (DNA methods). For HLA class II typing, cytotoxic test (cellular), MLC (serological), RFLP, SSO, SSP--PCR, and SBT (DNA methods) are used. DNA methods represent the modern trend in the area of HLA typing and it will probably replace larger part of other HLA typing techniques. In our article, we describe the principles of methods that are used for HLA typing.
HLA Antigens↗