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1.
Mol Neurobiol ; 56(8): 5304-5314, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30603956

RESUMO

Endothelial dysfunction is a key element in cerebral small vessel disease (CSVD), which may cause stroke and cognitive decline. Cyclic nucleotide signaling modulates endothelial function. The cyclic adenosine monophosphate-degrading enzyme phosphodiesterase 3 (PDE3) is an important treatment target which may be modulated by microRNAs (miRNAs) important for regulating gene expression. We aimed to identify PDE3-targeting miRNAs to highlight potential therapeutic targets for endothelial dysfunction and CSVD. PDE3-targeting miRNAs were identified by in silico analysis (TargetScan, miRWalk, miRanda, and RNA22). The identified miRNAs were ranked on the basis of TargetScan context scores and their expression (log2 read counts) in a human brain endothelial cell line (hCMEC/D3) described recently. miRNAs were subjected to co-expression meta-analysis (CoMeTa) to create miRNA clusters. The pathways targeted by the miRNAs were assigned functional annotations via the KEGG pathway and COOL. hCMEC/D3 cells were transfected with miRNA mimics miR-27a-3p and miR-222-3p, and the effect on PDE3A protein expression was analyzed by Western blotting. Only PDE3A is expressed in hCMEC/D3 cells. The in silico prediction identified 67 PDE3A-related miRNAs, of which 49 were expressed in hCMEC/D3 cells. Further analysis of the top two miRNA clusters (miR-221/miR-222 and miR-27a/miR-27b/miR-128) indicated a potential link to pathways relevant to cerebral and vascular integrity and repair. hCMEC/D3 cells transfected with miR-27a-3p and miR-222-3p mimics had reduced relative expression of PDE3A protein. PDE3A-related miRNAs miR-221/miR-222 and miR-27a/miR-27b/miR-128 are potentially linked to pathways essential for immune regulation as well as cerebral and vascular integrity/function. Furthermore, relative PDE3A protein expression was reduced by miR27a-3p and miR-222-3p.


Assuntos
Encéfalo/irrigação sanguínea , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Microvasos/citologia , Linhagem Celular , Sobrevivência Celular , DNA Complementar/genética , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , Neurônios/metabolismo
2.
Scand J Immunol ; 87(1): 46-53, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29125655

RESUMO

B cells have recently entered the stage as an important accessory player in type 1 diabetes (T1D) etiopathogenesis. Experimental studies suggest regulatory functions of vitamin D on B cells. However, only a few human studies, with considerable methodological limitations, have been conducted within this field. Our objective was to investigate whether higher 25-hydroxyvitamin D (25(OH)D) concentrations were inversely associated with ß-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma-associated antigen-2A (IA-2A). Further, we also wanted to examine the relationship between 25(OH)D and total antibody concentrations. We randomly selected 500 patients with newly diagnosed T1D and 500 siblings for 25(OH)D, antibody and genetic analysis from the population-based Danish Registry of Childhood and Adolescent Diabetes. The relative change (RC) in the mean concentration of GADA, IA-2A and antibody isotypes by a 10 nmol/l increase in 25(OH)D concentration was modelled by a robust log-normal regression model. We found no association between 25(OH)D and GADA [adjusted RC per 10 nmol/l increase: 1.00; 95% confidence interval (CI): 0.98-1.02] and IA-2A [adjusted RC per 10 nmol/l increase: 0.92; CI: 0.76-1.12]. Further, 25(OH)D was not associated with the total concentration of antibody isotypes [immunoglobulin (Ig)A, IgE, IgG and IgM]. All null findings were unaltered after adjustment for genetic variation in the vitamin D pathway. Physiological concentrations of 25(OH)D are unlikely to have a clinically important effect on antibody concentrations in a paediatric population of newly diagnosed patients with T1D and their healthy siblings.


Assuntos
Autoantígenos/sangue , Diabetes Mellitus Tipo 1/imunologia , Isotipos de Imunoglobulinas/sangue , Vitamina D/análogos & derivados , Estudos de Casos e Controles , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Feminino , Glutamato Descarboxilase/sangue , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/sangue , Irmãos , Vitamina D/sangue
3.
Diabet Med ; 34(3): 380-386, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27027777

RESUMO

AIM: To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. METHODS: In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations (n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. RESULTS: During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). CONCLUSION: We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes.


Assuntos
Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Adolescente , Adulto , Biomarcadores/sangue , Criança , Estudos de Coortes , Estudos Transversais , Dinamarca/epidemiologia , Complicações do Diabetes/mortalidade , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/mortalidade , Diabetes Mellitus Tipo 1/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Masculino , Mortalidade , Estudos Prospectivos , Sistema de Registros , Análise de Sobrevida , Adulto Jovem
4.
Scand J Immunol ; 80(6): 452-61, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25201044

RESUMO

The mechanisms by which antigen-specific T cells migrate to the islets of Langerhans in type 1 diabetes (T1D) are largely unknown. Chemokines attract immune cells to sites of inflammation. The aim was to elucidate the role of inflammatory chemokines in T1D at time of diagnosis. From a population-based registry of children diagnosed with T1D from 1997 to 2005, we studied five different inflammatory chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8). Four hundred and eighty-two cases and 479 sibling frequencies matched on age and sample year distribution were included. Patients showed lower levels of CCL4 compared to siblings, but this result was not significant after correction for multiple testing. CCL2, CCL3, CCL4 and CXCL8 levels were highest in the most recent cohorts (P < 0.01) in both patients and siblings. A significant seasonal variation - for most of the chemokines - was demonstrated with the highest level during the summer period in both patients and siblings. In addition, there was a significant inverse relationship between CCL4 levels and age. When comparing patients and siblings, remarkably few differences were identified, but interestingly chemokine levels varied with age, season and period for the entire study population. Such variations should be taken into account when studying chemokines in paediatric populations.


Assuntos
Quimiocina CCL2/sangue , Quimiocina CCL3/sangue , Quimiocina CCL4/sangue , Diabetes Mellitus Tipo 1/sangue , Interleucina-8/sangue , Irmãos , Adolescente , Fatores Etários , Autoanticorpos/sangue , Autoanticorpos/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Sistema de Registros , Estações do Ano , Fatores Sexuais , Fatores de Tempo
5.
Diabetologia ; 55(4): 996-1000, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22278338

RESUMO

AIMS/HYPOTHESIS: Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. METHODS: We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. RESULTS: Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. CONCLUSIONS/INTERPRETATION: The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.


Assuntos
Diabetes Mellitus Tipo 1/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
6.
Diabetes Res Clin Pract ; 96(2): 204-10, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22251574

RESUMO

AIMS: To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D. METHODS: T1D children (n=260, median age at diagnosis 9.4, range 0.9-14.7 years) were tested for GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q autoantibodies (A) at diagnosis, and 3-6 years after diagnosis when also fasting and stimulated RBF were determined. RESULTS: For every 1-year increase in age at diagnosis of TID, the odds of detectable C-peptide increased 1.21 (1.09, 1.34) times for fasting C-peptide and 1.28 (1.15, 1.42) times for stimulated C-peptide. Based on a linear model for subjects with no change in IA-2A levels, the odds of detectable C-peptide were 35% higher than for subjects whose IA-2A levels decreased by half (OR=1.35 (1.09, 1.67), p=0.006); similarly for ZnT8WA (OR=1.39 (1.09, 1.77), p=0.008) and ZnT8QA (OR=1.55 (1.06, 2.26) p=0.024). Such relationship was not detected for GADA or ZnT8RA. All OR adjusted for confounders. CONCLUSIONS: Age at diagnosis with T1D was the major predictor of detectable C-peptide 3-6 years post-diagnosis. Decreases in IA-2A, and possibly ZnT8A, levels between diagnosis and post-diagnosis were associated with a reduction in RBF post-diagnosis.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Adolescente , Proteínas de Transporte de Cátions/imunologia , Criança , Pré-Escolar , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Transportador 8 de Zinco
7.
Genes Immun ; 10 Suppl 1: S1-4, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19956093

RESUMO

The Type I Diabetes Genetics Consortium (T1DGC) is an international, multicenter research program with two primary goals. The first goal is to identify genomic regions and candidate genes whose variants modify an individual's risk of type I diabetes (T1D) and help explain the clustering of the disease in families. The second goal is to make research data available to the research community and to establish resources that can be used by, and that are fully accessible to, the research community. To facilitate the access to these resources, the T1DGC has developed a Consortium Agreement (http://www.t1dgc.org) that specifies the rights and responsibilities of investigators who participate in Consortium activities. The T1DGC has assembled a resource of affected sib-pair families, parent-child trios, and case-control collections with banks of DNA, serum, plasma, and EBV-transformed cell lines. In addition, both candidate gene and genome-wide (linkage and association) studies have been performed and displayed in T1DBase (http://www.t1dbase.org) for all researchers to use in their own investigations. In this supplement, a subset of the T1DGC collection has been used to investigate earlier published candidate genes for T1D, to confirm the results from a genome-wide association scan for T1D, and to determine associations with candidate genes for other autoimmune diseases or with type II diabetes that may be involved with beta-cell function.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/imunologia , Humanos , Internet , Publicações Periódicas como Assunto
8.
Genes Immun ; 10 Suppl 1: S128-31, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19956094

RESUMO

The Type I Diabetes Genetics Consortium (T1DGC) is an international collaboration whose primary goal is to identify genes whose variants modify an individual's risk of type I diabetes (T1D). An integral part of the T1DGC's mission is the establishment of clinical and data resources that can be used by, and that are fully accessible to, the T1D research community (http://www.t1dgc.org). The T1DGC has organized the collection and analyses of study samples and conducted several major research projects focused on T1D gene discovery: a genome-wide linkage scan, an intensive evaluation of the human major histocompatibility complex, a detailed examination of published candidate genes, and a genome-wide association scan. These studies have provided important information to the scientific community regarding the function of specific genes or chromosomal regions on T1D risk. The results are continually being updated and displayed (http://www.t1dbase.org). The T1DGC welcomes all investigators interested in using these data for scientific endeavors on T1D. The T1DGC resources provide a framework for future research projects, including examination of structural variation, re-sequencing of candidate regions in a search for T1D-associated genes and causal variants, correlation of T1D risk genotypes with biomarkers obtained from T1DGC serum and plasma samples, and in-depth bioinformatics analyses.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Fatores de Risco
9.
Genes Immun ; 10 Suppl 1: S49-53, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19956100

RESUMO

To reassess earlier suggested type I diabetes (T1D) associations of the insulin receptor substrate 1 (IRS1) and the paired domain 4 gene (PAX4) genes, the Type I Diabetes Genetics Consortium (T1DGC) evaluated single-nucleotide polymorphisms (SNPs) covering the two genomic regions. Sixteen SNPs were evaluated for IRS1 and 10 for PAX4. Both genes are biological candidate genes for T1D. Genotyping was performed in 2300 T1D families on both Illumina and Sequenom genotyping platforms. Data quality and concordance between the platforms were assessed for each SNP. Transmission disequilibrium testing neither show T1D association of SNPs in the two genes, nor did haplotype analysis. In conclusion, the earlier suggested associations of IRS1 and PAX4 to T1D were not supported, suggesting that they may have been false positive results. This highlights the importance of thorough quality control, selection of tagging SNPs, more than one genotyping platform in high throughput studies, and sufficient power to draw solid conclusions in genetic studies of human complex diseases.


Assuntos
Diabetes Mellitus Tipo 1/genética , Proteínas de Homeodomínio/genética , Proteínas Substratos do Receptor de Insulina/genética , Fatores de Transcrição Box Pareados/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Humanos
10.
Genes Immun ; 10 Suppl 1: S64-8, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19956104

RESUMO

As part of its efforts to identify genes affecting the risk of type I diabetes (T1D), the Type I Diabetes Genetics Consortium commissioned an extensive survey of variants associated with genes reported earlier to have an association with disease susceptibility. In this report, we present the analysis of a set of single-nucleotide polymorphisms (SNPs) within and flanking the IL12B gene, which encodes the p40 subunit of the cytokines interleukin (IL)-12 and IL-23. No SNP showed individually significant association in the population as a whole. Nevertheless, subjects stratified according to genotype at the earlier reported SNP in the IL12B 3'UTR, rs3212227, confirmed small, but significant, differences in age of disease onset with a relative hazard=0.88 (P=0.005). The protective effect of rs3212227 allele 2 was gender specific (P=0.004 overall and P=0.0003 when unaffected siblings were considered). Among females, the 2.2 genotype was more protective, with relative hazard=0.75. We conclude that while there was no major effect of IL12B polymorphisms on T1D susceptibility in the entire study group, they have an impact on a subset of at-risk individuals.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Subunidade p40 da Interleucina-12/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Subunidade p40 da Interleucina-12/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Caracteres Sexuais , Fatores Sexuais , Adulto Jovem
11.
Genes Immun ; 10(4): 323-33, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19295542

RESUMO

The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1(*)03-DQA1(*)0501-DQB1(*)0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1(*)0401-DQA1(*)03-DQB1(*)0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1(*)0401-DQA1(*)03-DQB1(*)0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Serina Endopeptidases/genética , Alelos , Diabetes Mellitus Tipo 1/imunologia , Feminino , Frequência do Gene/genética , Genótipo , Haplótipos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único/genética
12.
Diabetes Obes Metab ; 11(3): 196-203, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19215277

RESUMO

AIMS/HYPOTHESIS: The suppressor of cytokine signalling 1 (SOCS1) is a natural inhibitor of cytokine and insulin signalling pathways and may also play a role in obesity. In addition, SOCS1 is considered a candidate gene in the pathogenesis of both type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective was to perform mutation analysis of SOCS1 and to test the identified variations for association to T2D-related quantitative traits, T2D or T1D. METHODS: Mutation scanning was performed by direct sequencing in 27 white Danish subjects. Genotyping was carried out by TaqMan allelic discrimination. A total of more than 8100 individuals were genotyped. RESULTS: Eight variations were identified in the 5' untranslated region (UTR) region. Two of these had allele frequencies below 1% and were not further examined. The six other variants were analysed in groups of T1D families (n = 1461 subjects) and T2D patients (n = 1430), glucose tolerant first-degree relatives of T2D patients (n = 212) and normal glucose tolerant (NGT) subjects. The rs33977706 polymorphism (-820G > T) was associated with a lower body mass index (BMI) (p = 0.004). In a second study (n = 4625 NGT subjects), significant associations of both the rs33977706 and the rs243330 (-1656G > A) variants to obesity were found (p = 0.047 and p = 0.015) respectively. The rs33977706 affected both binding of a nuclear protein to and the transcriptional activity of the SOCS1 promoter, indicating a relationship between this polymorphism and gene regulation. CONCLUSIONS/INTERPRETATION: This study demonstrates that functional variations in the SOCS1 promoter may associate with alterations in BMI in the general white population.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Resistência à Insulina/genética , Obesidade/genética , Polimorfismo Genético/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/metabolismo
13.
Diabetes Obes Metab ; 11 Suppl 1: 60-6, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19143816

RESUMO

AIM: To develop novel methods for identifying new genes that contribute to the risk of developing type 1 diabetes within the Major Histocompatibility Complex (MHC) region on chromosome 6, independently of the known linkage disequilibrium (LD) between human leucocyte antigen (HLA)-DRB1, -DQA1, -DQB1 genes. METHODS: We have developed a novel method that combines single nucleotide polymorphism (SNP) genotyping data with protein-protein interaction (ppi) networks to identify disease-associated network modules enriched for proteins encoded from the MHC region. Approximately 2500 SNPs located in the 4 Mb MHC region were analysed in 1000 affected offspring trios generated by the Type 1 Diabetes Genetics Consortium (T1DGC). The most associated SNP in each gene was chosen and genes were mapped to ppi networks for identification of interaction partners. The association testing and resulting interacting protein modules were statistically evaluated using permutation. RESULTS: A total of 151 genes could be mapped to nodes within the protein interaction network and their interaction partners were identified. Five protein interaction modules reached statistical significance using this approach. The identified proteins are well known in the pathogenesis of T1D, but the modules also contain additional candidates that have been implicated in beta-cell development and diabetic complications. CONCLUSIONS: The extensive LD within the MHC region makes it important to develop new methods for analysing genotyping data for identification of additional risk genes for T1D. Combining genetic data with knowledge about functional pathways provides new insight into mechanisms underlying T1D.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Antígenos HLA/genética , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único/genética , Apolipoproteínas/genética , Apolipoproteínas M , Antígenos CD4/genética , Proteínas de Ligação ao Cálcio , Cromossomos Humanos Par 6/genética , Proteínas de Ligação a DNA/genética , Genótipo , Proteína HMGB1/genética , Humanos , Lipocalinas , Proteínas dos Microfilamentos , Mapeamento de Interação de Proteínas , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética
15.
Genes Immun ; 8(3): 232-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17330137

RESUMO

We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most likely candidate genes influencing beta-cell function in this region. Two array-based approaches were used, a rat insulinoma cell line (INS-1alphabeta) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1beta (IL-1beta) as well as human pancreatic islets stimulated with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved in cytokine signaling, oxidative phosphorylation, defense responses and apoptosis. The analyses, furthermore, revealed several transcription factor binding sites shared by the differentially expressed genes and by genes demonstrating highly similar expression profiles with these genes. Comparable findings in the rat beta-cell line and human islets support the validity of the methods used and support this as a valuable approach for gene mapping and identification of genes with potential functional significance in T1D, within a region of linkage.


Assuntos
Cromossomos Humanos Par 21/genética , Diabetes Mellitus Tipo 1/genética , Ilhotas Pancreáticas/metabolismo , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Criança , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Técnicas In Vitro , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulinoma/genética , Interleucina-1beta/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Ratos , Transativadores/genética
16.
Diabetologia ; 50(3): 676-81, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17216280

RESUMO

AIMS/HYPOTHESIS: Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. MATERIALS AND METHODS: Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 microg/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. RESULTS: A high level of PIMT protein was detected in beta cells. CGP3466B induced a two- to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokine-induced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6+/-9.0 vs 84.3+/-6.8 vs 106.6+/-13.5 days, respectively; p<0.01 for high-dose vs low-dose and control groups), the severity of the disease was reduced (glucose 22.2+/-3.2 vs 16.9+/-2.6 vs 15.8+/-2.7 mmol; p<0.01 for high- and low-dose groups vs control group) and residual beta cells were more frequently identified (43% vs 71% vs 86%; p<0.05 for high-dose vs control group) in the treated animals. CONCLUSIONS/INTERPRETATION: The results support a role for post-translational modifications and PIMT in the development of type 1 diabetes in the diabetes-prone BB rat, and perhaps also in humans.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Análise de Sequência com Séries de Oligonucleotídeos , Oxepinas/farmacologia , Oxepinas/uso terapêutico , Pâncreas/citologia , Pâncreas/enzimologia , Proteína D-Aspartato-L-Isoaspartato Metiltransferase/genética , Ratos , Ratos Endogâmicos BB , Valores de Referência
17.
Scand J Immunol ; 64(6): 639-45, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17083620

RESUMO

Secretagogin is a newly identified calcium-binding protein selectively expressed in neuroendocrine tissue and pancreatic beta-cells. The function of secretagogin is unknown, but it has been suggested in beta-cells to influence calcium-influx, insulin secretion and proliferation, and has been observed downregulated in diabetes-prone BB rat islets exposed to cytokines. In the present study, we identified and characterized promoter activity of a human 1498 bp sequence upstream the transcription start site. The promoter sequence showed subtle but significant regulation by glucose within the normo-physiological range. Glucose also led to changes in expression of secretagogin protein in INS-1e cells, but not in primary cells from non-diabetes-prone Wistar Furth rats. No effects of cytokines neither on promoter activity nor protein expression were observed. The promoter region was furthermore screened by direct sequencing, and 11 polymorphisms were identified. Genotyping in a large homogenous Type 1 diabetes (T1D) family collection did not reveal association with T1D.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Regulação da Expressão Gênica , Regiões Promotoras Genéticas/fisiologia , Regiões 5' não Traduzidas/genética , Regiões 5' não Traduzidas/fisiologia , Animais , Sequência de Bases , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Citocinas/farmacologia , Diabetes Mellitus Tipo 1/genética , Glucose/farmacologia , Humanos , Ilhotas Pancreáticas/metabolismo , Dados de Sequência Molecular , Polimorfismo Genético , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ratos , Secretagoguinas , Sítio de Iniciação de Transcrição
18.
Genes Immun ; 7(4): 316-21, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16691186

RESUMO

Type II diabetes is caused by a failure of the pancreatic beta-cells to compensate for insulin resistance leading to hyperglycaemia. There is evidence for an essential role of an increased beta-cell apoptosis in type II diabetes. High glucose concentrations induce IL-1beta production in human beta-cells, Fas expression and concomitant apoptosis owing to a constitutive expression of FasL. FASL and FAS map to loci linked to type II diabetes and estimates of insulin resistance, respectively. We have tested two functional promoter polymorphisms, FAS-670 G>A and FASL-844C>T as well as a microsatellite in the 3' UTR of FASL for association to type II diabetes in 549 type II diabetic patients and 525 normal-glucose-tolerant (NGT) control subjects. Furthermore, we have tested these polymorphisms for association to estimates of beta-cell function and insulin resistance in NGT subjects. We found significant association to type II diabetes for the allele distribution of the FASL microsatellite (P-value 0.02, Bonferroni corrected). The FAS-670G>A was associated with homeostasis model assessment insulin resistance index and body mass index (P-values 0.02 and 0.02). We conclude that polymorphisms of FASL and FAS associate with type II diabetes and estimates of insulin resistance in Danish white subjects.


Assuntos
Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Glicoproteínas de Membrana/genética , Repetições de Microssatélites , Receptores do Fator de Necrose Tumoral/genética , Fatores de Necrose Tumoral/genética , Regiões 3' não Traduzidas/genética , Adulto , Idoso , Apoptose , Dinamarca , Proteína Ligante Fas , Feminino , Humanos , Células Secretoras de Insulina/citologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Característica Quantitativa Herdável , Receptor fas
19.
Diabetologia ; 49(6): 1179-82, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16575558

RESUMO

AIMS/HYPOTHESIS: In patients with Down's syndrome, dogma has long held that the prevalence of diabetes is increased. The aim of the present study was to determine the actual prevalence of Down's syndrome among type 1 diabetic patients. SUBJECTS, MATERIALS AND METHODS: The background population included all children born in Denmark between 1981 and 2000. Registry-validated and clinical data on type 1 diabetes and Down's syndrome diagnoses were obtained from the National Disease Register and Danish Cytogenetic Central Register, respectively. RESULTS: The prevalence of Down's syndrome in the background population was 0.09%, whereas we identified a prevalence of Down's syndrome in type 1 diabetes patients of 0.38% (95% CI 0.17-0.75), corresponding to a 4.2-fold increased prevalence compared with the background population (p = 7.3 x 10(-5)). CONCLUSIONS/INTERPRETATION: To the best of our knowledge this is the first population-based study addressing the prevalence of Down's syndrome among verified type 1 diabetes patients. A more than fourfold increased prevalence of Down's syndrome among type 1 diabetes patients supports the notion that genes on chromosome 21 may confer risk for type 1 diabetes, probably also in the general population.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Síndrome de Down/epidemiologia , Adolescente , Adulto , Idade de Início , Autoanticorpos/sangue , Criança , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 1/complicações , Síndrome de Down/complicações , Humanos , Hipoglicemiantes/uso terapêutico , Lactente , Insulina/uso terapêutico , Prevalência , Sistema de Registros
20.
Genes Immun ; 7(2): 130-40, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16395395

RESUMO

First generation linkage disequilibrium (LD) and haplotype maps of the human major histocompatibility complex (MHC) have been generated in order to aid the unraveling of the numerous disease predisposing genes in this region by offering a first set of haplotype tagSNPs. Several parameters, like the population studied, the marker map used, the density of polymorphisms and the applied algorithm, are influencing the appearance of haplotype blocks and selection of tags. The MHC comprises a limited number of ancestral, conserved haplotypes. We address the impact of the underlying HLA haplotypes on the LD patterns, haplotype blocks and tag selection throughout the entire extended MHC (xMHC) by studying DR-DQ haplotypes, mainly those carrying DRB1*03 and DRB1*04 alleles. We observed significantly different degree and extent of LD calculated on different HLA backgrounds, as well as variation in the size and boundaries of the defined haplotype and tags selected. Our results demonstrate that the underlying ancestral HLA haplotypic architecture is yet another parameter to take into consideration when constructing LD maps of the xMHC. This may be essential for mapping of disease susceptibility genes since many diseases are associated with and map on particular HLA haplotypes.


Assuntos
Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Haplótipos , Desequilíbrio de Ligação , Complexo Principal de Histocompatibilidade/genética , Mapeamento Cromossômico , Marcadores Genéticos , Humanos , Polimorfismo de Nucleotídeo Único
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