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1.
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
2.
Diabetologia ; 54(1): 69-72, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20886203

RESUMO

AIMS: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study. METHODS: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA1(c) were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models. RESULTS: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA1(c)). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG. CONCLUSIONS/INTERPRETATION: Mean glycaemia and HbA1(c) show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes.


Assuntos
Glicemia/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobina A Glicada/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Humanos , Período Pós-Prandial , Fatores de Risco
3.
Diabetologia ; 53(8): 1608-11, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20396998

RESUMO

AIMS/HYPOTHESIS: Real-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes. METHODS: In the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c). RESULTS: We found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring. CONCLUSIONS/INTERPRETATION: Even though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements.


Assuntos
Glicemia/análise , Hemoglobina A Glicada/análise , Adulto , Glicemia/metabolismo , Jejum/sangue , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial , Valores de Referência
4.
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
5.
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
6.
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
7.
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
9.
Diabetologia ; 51(5): 836-45, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18311556

RESUMO

AIMS/HYPOTHESIS: Events during fetal life may in critical time windows programme tissue development leading to organ dysfunction with potentially harmful consequences in adulthood such as diabetes. In rats, the beta cell mass of progeny from dams fed with a low-protein (LP) diet during gestation is decreased at birth and metabolic perturbation lasts through adulthood even though a normal diet is given after birth or after weaning. Maternal and fetal plasma taurine levels are suboptimal. Maternal taurine supplementation prevents these induced abnormalities. In this study, we aimed to reveal changes in gene expression in fetal islets affected by the LP diet and how taurine may prevent these changes. METHODS: Pregnant Wistar rats were fed an LP diet (8% [wt/wt] protein) supplemented or not with taurine in the drinking water or a control diet (20% [wt/wt] protein). At 21.5 days of gestation, fetal pancreases were removed, digested and cultured for 7 days. Neoformed islets were collected and transcriptome analysis was performed. RESULTS: Maternal LP diet significantly changed the expression of more than 10% of the genes. Tricarboxylic acid cycle and ATP production were highly targeted, but so too were cell proliferation and defence. Maternal taurine supplementation normalised the expression of all altered genes. CONCLUSIONS/INTERPRETATION: Development of the beta cells and particularly their respiration is modulated by the intrauterine environment, which may epigenetically modify expression of the genome and programme the beta cell towards a pre-diabetic phenotype. This mis-programming by maternal LP diet was prevented by early taurine intervention.


Assuntos
Feto/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Ilhotas Pancreáticas/embriologia , Taurina/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Suplementos Nutricionais , Feminino , Glicólise/genética , Células Secretoras de Insulina/enzimologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Ratos , Ratos Wistar , Taurina/sangue , Útero/fisiologia
10.
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
11.
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
12.
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
13.
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
14.
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
15.
Diabetes Obes Metab ; 8(1): 75-82, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16367885

RESUMO

AIMS: Type 1 diabetes mellitus (T1DM) is a chronic disorder primarily triggered by environmental and immunological factors in genetically susceptible individuals. Despite the fact that there are indications of common aetiological features of T1DM and type 2 diabetes (T2DM), variation in genes involved in insulin secretion and insulin signalling has to a large extent been ignored as potential modifiers in the pathogenesis of T1DM. Recent studies suggest, however, that proven T2DM susceptibility gene variants may be involved in the pathogenesis of T1DM. The objective of this study was to estimate the impact of four selected amino acid polymorphisms -IRS-1 Gly972Arg, Kir6.2 Glu23Lys, HNF-1alpha Ala98Val and PPARgamma2 Pro12Ala in a Danish population of T1DM families. METHODS: All variants were genotyped in 490 simplex- and multiplex-T1DM families applying polymerase chain reaction-restriction fragment length polymorphism, and results were evaluated by means of a transmission disequilibrium test (TDT) analysis. RESULTS: TDT analysis revealed that the Arg972 IRS-1, the Lys23 Kir6.2 and the Val98 HNF-1alpha variants were transmitted from heterozygous parents to affected probands at frequencies of 49.1%, 47.0% and 54.1%, respectively (p > 0.05 for all). This was similar to the rate of transmission to unaffected siblings. The transmission rate of the Ala12 PPARgamma2 variant to affected probands was 46.5% (p > 0.05) which differed significantly from the transmission to unaffected offspring (p = 0.024). A combined analysis of the present and published pertinent data of 1691 transmissions showed a significantly decreased transmission of the PPARgamma2 Ala12 allele to affected probands (p = 0.0045). CONCLUSIONS: The Pro12Ala variant of PPARgamma2 is associated with T1DM, the minor Ala allele conferring a reduced risk. This same finding has been reported in patients with T2DM.


Assuntos
Diabetes Mellitus/genética , Fator 1-alfa Nuclear de Hepatócito/genética , PPAR gama/genética , Fosfoproteínas/genética , Polimorfismo Genético/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adolescente , Adulto , Aminoácidos/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Saúde da Família , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genótipo , Antígeno HLA-DR3/genética , Antígeno HLA-DR4/genética , Heterozigoto , Humanos , Lactente , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina , Pais , Irmãos
17.
Acta Diabetol ; 42(2): 95-8, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15944843

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease in genetically predisposed individuals characterised by selective destruction of the beta-cells. Development of diabetes is in the asymptomatic pre-diabetic period characterised by impaired first-phase insulin response and the first clinical symptom is elevated blood glucose (BG). It is still uncertain whether stress or incidental hyperglycaemia can be regarded as predictors for development of T1D or not, even when immunologic and genetic markers for T1D are considered. The aim of this study was to investigate if there was any relationship between elevated BG in 30-day-old anaesthetised pre-diabetic diabetes-prone Bio Breeding (BB-DP) rats and later development of diabetes. Rats anaesthetised by intraperitoneal (ip) injection for islet transplantation displayed significantly higher BG values (Delta1.27 mmol/l, p=8.27x10(-12)) compared to non-anaesthetised non-transplanted rats, indicating that ip injection and/or anaesthesia induce a higher BG level. Linear regression analysis of BG and time of onset of diabetes in transplanted and non-transplanted BB-DP rats revealed no correlation (R(2) at 0.0075 and 0.0324 and p-values at 0.56 and 0.23 respectively). We were not able to identify any association or correlation between the induced temporary hyperglycaemia in 30-day-old BB-DP rats and later development of diabetes.


Assuntos
Anestesia/efeitos adversos , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Hiperglicemia/etiologia , Animais , Hiperglicemia/epidemiologia , Estado Pré-Diabético , Prevalência , Ratos , Ratos Endogâmicos BB
18.
Br J Nutr ; 93(3): 309-16, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15877869

RESUMO

Epidemiological studies have indicated that malnutrition during early life may programme chronic degenerative disease in adulthood. In an animal model of fetal malnutrition, rats received an isoenergetic, low-protein (LP) diet during gestation. This reduced fetal beta-cell proliferation and insulin secretion. Supplementation during gestation with taurine prevented these alterations. Since proteases are involved in secretion and proliferation, we investigated which proteases were associated with these alterations and their restoration in fetal LP islets. Insulin secretion and proliferation of fetal control and LP islets exposed to different protease modulators were measured. Lactacystin and calpain inhibitor I, but not isovaleryl-L-carnitine, raised insulin secretion in control islets, indicating that proteasome and cysteinyl cathepsin(s), but not mu-calpain, are involved in fetal insulin secretion. Insulin secretion from LP islets responded normally to lactacystin but was insensitive to calpain inhibitor I, indicating a loss of cysteinyl cathepsin activity. Taurine supplementation prevented this by restoring the response to calpain inhibitor I. Control islet cell proliferation was reduced by calpain inhibitor I and raised by isovaleryl-L-carnitine, indicating an involvement of calpain. Calpain activity appeared to be lost in LP islets and not restored by taurine. Most modifications in the mRNA expression of cysteinyl cathepsins, calpains and calpastatin due to maternal protein restriction were consistent with reduced protease activity and were restored by taurine. Thus, maternal protein restriction affected cysteinyl cathepsins and the calpain-calpastatin system. Taurine normalised fetal LP insulin secretion by protecting cysteinyl cathepsin(s), but the restoration of LP islet cell proliferation by taurine did not implicate calpains.


Assuntos
Acetilcisteína/análogos & derivados , Dieta com Restrição de Proteínas , Transtornos da Nutrição Fetal/fisiopatologia , Insulina/metabolismo , Ilhotas Pancreáticas/embriologia , Peptídeo Hidrolases/fisiologia , Acetilcisteína/farmacologia , Animais , Proteínas de Ligação ao Cálcio/fisiologia , Calpaína/fisiologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Glicoproteínas/farmacologia , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Troca Materno-Fetal , Peptídeo Hidrolases/genética , Gravidez , Complexo de Endopeptidases do Proteassoma/biossíntese , Complexo de Endopeptidases do Proteassoma/genética , Análise Serial de Proteínas , Ratos , Ratos Wistar , Taurina/farmacologia
19.
J Med Genet ; 42(1): 17-25, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15635070

RESUMO

BACKGROUND: Results of a Scandinavian genome scan in type 1 diabetes mellitus (T1D) have recently been reported. Among the novel, not previously reported chromosomal regions showing linkage to T1D was a region on chromosome 21. OBJECTIVE: To fine map this region on chromosome 21. METHODS AND RESULTS: The linked region was initially narrowed by linkage analysis typing microsatellite markers. Linkage was significantly increased, with a peak NPL score of 3.61 (p = 0.0002), suggesting the presence of one or several T1D linked genes in the region. The support interval for linkage of 6.3 Mb was then studied by linkage disequilibrium (LD) mapping with gene based single nucleotide polymorphisms (SNPs). Thirty two candidate genes were identified in this narrowed region, and LD mapping was carried out with SNPs in coding regions (cSNPs) of all these genes. However, none of the SNPs showed association to T1D in the complete material, whereas some evidence for association to T1D of variants of the TTC3, OLIG2, KCNE1, and CBR1 genes was observed in conditioned analyses. The disease related LD was further assessed by a haplotype based association study, in which several haplotypes showed distorted transmission to diabetic offspring, substantiating a possible T1D association of the region. CONCLUSIONS: Although a single gene variant responsible for the observed linkage could not be identified, there was evidence for several combinations of markers, and for association of markers in conditioned analyses, supporting the existence of T1D susceptibility genes in the region.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 21 , Diabetes Mellitus Tipo 1/genética , DNA/genética , DNA/isolamento & purificação , Dinamarca , Genoma Humano , Genótipo , Humanos , Repetições de Microssatélites/genética , Países Escandinavos e Nórdicos
20.
Diabetologia ; 47(12): 2185-99, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15605246

RESUMO

AIM/HYPOTHESIS: Maturation of the beta cells in the islets of Langerhans is dependent upon sequential activation of different transcription factors such as Pdx-1 and Nkx6.1. This maturation is associated with an acquired sensitivity to cytokines and may eventually lead to type 1 diabetes. The aims of this study were to characterise changes in mRNA expression during beta cell maturation as well as after interleukin-1beta (IL-1beta) exposure. METHODS: Transcriptome analyses were performed on two phenotypes characterised as a glucagon-producing pre-beta-cell phenotype (NHI-glu), which matures to an IL-1beta-sensitive insulin-producing beta cell phenotype (NHI-ins). Beta cell lines over-expressing Pdx-1 or Nkx6.1, respectively, were used for functional characterisation of acquired IL-1beta sensitivity. RESULTS: During beta cell maturation 98 fully annotated mRNAs changed expression levels. Of these, 50 were also changed after 24 h of IL-1beta exposure. In addition, 522 and 197 fully annotated mRNAs, not affected by maturation, also changed expression levels following IL-1beta exposure of the beta cell and the pre-beta-cell phenotype, respectively. Beta cell maturation was associated with an increased expression of Nkx6.1, whereas both Pdx-1 and Nkx6.1 expression were decreased following IL-1beta exposure. Over-expression of Nkx6.1 or Pdx-1 in cell lines resulted in a significantly increased sensitivity to IL-1beta. CONCLUSIONS/INTERPRETATION: These results suggest that the final beta cell maturation accompanied by increased IL-1beta sensitivity is, in part, dependent upon the expression of genes regulated by Pdx-1 and Nkx6.1. Future classification of the genes regulated by these transcription factors and changed during beta cell maturation should elucidate their role in the acquired sensitivity to IL-1beta and may be helpful in identifying new targets for intervention/prevention strategies.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Interleucina-1/farmacologia , Ilhotas Pancreáticas/fisiologia , Transativadores/genética , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA , Ilhotas Pancreáticas/efeitos dos fármacos , Transplante das Ilhotas Pancreáticas , RNA Complementar/genética , RNA Mensageiro/genética , Ratos , Transcrição Genética
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