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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
10.
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
11.
Diabetologia ; 47(7): 1273-1277, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15249995

RESUMO

AIMS/HYPOTHESIS: Beta cell loss in Type 1 and Type 2 diabetes mellitus may result from apoptosis and necrosis induced by inflammatory mediators. The suppressor of cytokine signalling (SOCS)-3 is a natural inhibitor of cytokine signalling and also influences insulin signalling. SOCS3 could therefore be a candidate gene in the development of Type 1 and Type 2 diabetes mellitus. METHODS: Mutation analysis of the SOCS3 gene was performed in 21 patients with Type 1 diabetes mellitus and in seven healthy subjects. An identified promoter variant was examined in (i) 250 families with Type 1 diabetic family members (1097 individuals); (ii) 212 glucose-tolerant first-degree relatives of Type 2 diabetic patients; and (iii) 370 population-based young, healthy subjects who were unrelated. RESULTS: Three mutations were identified in the promoter region, but none in the coding region or the 3'UTR. Two of the three mutations had allele frequencies below 1% whereas the C -920-->A substitution had a minor allele frequency of 8%. In the group of young healthy subjects the insulin sensitivity index was higher among homozygous carriers of the A-allele than among heterozygous and wild-type subjects ( p=0.027, uncorrected). The same trend was found in the group of first-degree relatives of Type 2 diabetic patients. No association or linkage was found to Type 1 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Homozygosity for the A-allele of the C -920-->A promoter polymorphism of the SOCS3 gene may be associated with increased whole-body insulin sensitivity, but deserves further investigation.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Insulina/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Primers do DNA , Família , Humanos , Lactente , Reação em Cadeia da Polimerase , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina
13.
Genes Immun ; 3(7): 430-2, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12424626

RESUMO

Cytokine-induced beta-cell death is an important factor in the pathogenesis of type 1 diabetes mellitus (T1DM). The transcription factor NFkappaB plays an important role in cytokine-induced gene activation. Hence, NFKB1 is a possible candidate gene for T1DM disposition. A polymorphic (CA) dinucleotide repeat microsatellite has been identified near the NFKB1 gene. In a recent case-control study certain alleles of this NFKB1 microsatellite marker showed strong association to T1DM. The aim of our study was to investigate whether the association between the NFKB1 marker and T1DM could be confirmed in a Danish family collection. No T1DM association for any allele of the NFKB1 microsatellite marker could however be demonstrated in Danish T1DM families. In conclusion, we could not confirm the highly significant T1DM association of certain alleles of the NFKB1 marker previously reported.


Assuntos
Diabetes Mellitus Tipo 1/genética , NF-kappa B/genética , Repetições de Dinucleotídeos , Marcadores Genéticos , Predisposição Genética para Doença , Humanos
14.
Cytokine ; 12(2): 171-5, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10671304

RESUMO

The molecules of the interleukin 1 (IL-1) system have been suggested to play a role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM), and polymorphisms in the genes encoding IL-1beta (IL1B), the IL-1 Type 1 receptor (IL1RTI) and the IL-1 receptor antagonist (IL1RN) molecules have been associated with IDDM in case-control studies. It can be difficult to exclude selection biases in case-control studies leading to spurious association. This risk is eliminated when using the transmission disequilibrium test (TDT). Hence, by means of the TDT we have investigated four intragenic IL-1 gene-cluster polymorphisms, the IL1B AvaI, the IL1B TaqI, the IL1RTI PstI and the IL1RN 2(nd)intron polymorphisms, for linkage and intra-familial association with IDDM in Danish IDDM multiplex family material comprising 245 families. We found no evidence for overall linkage or intra-familial association between any of the polymorphisms and IDDM. In addition, we did not find linkage between any of the polymorphisms and IDDM in HLA-DR3/4 heterozygous or HLA-non-DR3/4 heterozygous IDDM subjects, respectively. In conclusion, by means of intra-familial TDT analysis we found no linkage or intra-familial association between IDDM and the four IL-1 gene-cluster polymorphisms in Danish IDDM multiplex family material.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Interleucina-1/genética , Desequilíbrio de Ligação , Família Multigênica , Polimorfismo Genético , Dinamarca , Feminino , Antígeno HLA-DR3/genética , Antígeno HLA-DR4/genética , Heterozigoto , Humanos , Masculino , Polimorfismo de Fragmento de Restrição
15.
Genes Immun ; 1(8): 495-500, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11197691

RESUMO

The human interleukin-1 type I receptor (IL-1RI) is the signal transducing receptor for IL-1, a principal proinflammatory cytokine, which is cytotoxic to pancreatic islet beta cells. The IL-1RI gene, IL1R1, maps to chromosome 2q12. We have previously examined part of the IL1R1 promoter region and in the present study we further characterized the promoter region demarcating exon 1B and 1C by sequencing and mutation scanning. New sequence was obtained 1762 bp upstream and 1609 bp downstream the known region. Within this sequence, we identified four frequent single nucleotide polymorphisms (SNPs). PCR-based RFLP assays were established and three of the polymorphisms were typed in a Danish Type 1 (insulin-dependent) diabetes mellitus (T1DM) family collection comprising 103 simplex and 150 sib-pair affected families. Linkage was evaluated by the sib-TDT (transmission disequilibrium test). One of the polymorphisms, defined by a Hinfl RFLP assay, demonstrated linkage to T1DM, P(sTDT) = 0.026. Random transmission was observed to unaffected offspring from heterozygous parents, P = 0.87. No evidence for positive linkage was seen for the other tested polymorphisms, P = 0.14 and P = 0.21, respectively. To evaluate the possible functional significance of the Hinfl polymorphism, we measured circulating IL-1RI plasma level in 30 T1DM patients and in 30 control subjects--10 with each genotype in both groups. Significant differences in plasma levels in relation to genotype--independent of disease status--were found (P = 0.04). In both diabetic and non-diabetic subjects, the wt/wt genotype correlated with the highest IL-1RI plasma level, whereas the plasma levels were lowest for the mt/mt genotype.


Assuntos
Regiões 5' não Traduzidas , Diabetes Mellitus Tipo 1/genética , Ligação Genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Receptores de Interleucina-1/genética , Sequência de Bases , DNA Complementar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Receptores de Interleucina-1/sangue , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição AP-1/metabolismo
16.
Hum Immunol ; 51(1): 41-8, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8911996

RESUMO

The polygenic susceptibility to type 1 diabetes is well established and recent studies have demonstrated linkage of a further locus on chromosome 2q to disease. We have studied a polymorphism of the interleukin-1 receptor type 1 gene (IL1R1) on chromosome 2q in type 1 diabetic and control subjects from Finland, the United Kingdom, South India: three populations in which the risk of disease varies from very high to very low. In the medium-risk U.K. population we find a very strong association of IL1R1 with type 1 diabetes (p = 0.0002) but we find no overall association in either the high-risk Finnish or low-risk South-Indian populations. However, we do find heterogeneity of risk at IL1R1 amongst Finnish diabetic subjects according to the possession of HLA-DR associated susceptibility (p = 0.0001); there is an association with IL1R1 in only those Finnish diabetic subjects who do not possess high-risk HLA-DR4 or DR3 haplotypes (p = 0.006), as recently demonstrated for the insulin gene region in this population. We find no such heterogeneity of risk in either the U.K. or South-Indian populations. This study further demonstrates the genetic heterogeneity of disease susceptibility between and within populations and also supports the hypothesis of an interaction of the IL1R1 locus with genes within the HLA and insulin gene regions in the susceptibility to type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Receptores de Interleucina-1/genética , Adolescente , Alelos , Criança , Suscetibilidade a Doenças , Feminino , Antígenos HLA-DQ/análise , Cadeias beta de HLA-DQ , Antígenos HLA-DR/análise , Humanos , Masculino
19.
Cytokine ; 7(7): 727-33, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8580383

RESUMO

We have identified two PstI polymorphisms of the interleukin 1 receptor type I gene (IL1RI). One of these (RFLP-A) showed significant association to IDDM (P = 0.027), whereas no difference between patients and control subjects was found for RFLP-B (p = 0.42). RFLP-A was physically mapped to the 5'UTR of the gene. We sequenced and analysed a 411 bp region of a putative promotor region (P2) around RFLP-A. RFLP-A was due to a C to T transition in exon 1B of the IL1RI gene. This single-base mutation did not affect any known transcription factor recognition sequence or the predicted secondary mRNA structure. In addition, we found two other single-base substitutions in more than one individual. Neither of these showed specific disease association or absolute linkage with the RFLP-A.


Assuntos
Diabetes Mellitus Tipo 1/genética , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Receptores de Interleucina-1/genética , Alelos , Sequência de Bases , Sequência Consenso , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Família Multigênica
20.
Transplantation ; 59(1): 16-20, 1995 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-7839423

RESUMO

Oxidative damage is thought to play an important role in ischemia/reperfusion injury, including the outcome of transplantation of the liver and intestine. We have investigated oxidative DNA damage after combined transplantation of the liver and small intestine in 5 pigs. DNA damage was estimated from the urinary excretion of the repair product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). In the first 1-3 hr after reperfusion of the grafts, 8-oxodG excretion was increased 2.9-fold (1.7-4.1; 95% confidence intervals; P < 0.05). A control experiment included sham surgery with clamping of the suprarenal inferior caval vein in 2 pigs during steady state infusion of 8-oxodG. While the caval vein was clamped, the urinary excretion of 8-oxodG was almost blocked, whereas after removal of the clamp, the excretion returned to and did not exceed the preclamp levels. In a separate experiment with 2 pigs, the elimination of injected 8-oxodG was shown to adhere to first-order kinetics with a clearance and a terminal elimination half-life of approximately 4 ml min-1 kg-1 and 2 1/2 hr, respectively. The injected dose was completely excreted into the urine within 4 hr. It is concluded that substantial oxidative damage to DNA results from reperfusion of transplanted small intestine and liver in pigs, as estimated from the readily excreted repair product 8-oxodG.


Assuntos
Dano ao DNA , Intestino Delgado/transplante , Transplante de Fígado , Traumatismo por Reperfusão/metabolismo , 8-Hidroxi-2'-Desoxiguanosina , Animais , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Intestino Delgado/irrigação sanguínea , Intestino Delgado/metabolismo , Fígado/irrigação sanguínea , Fígado/metabolismo , Estresse Oxidativo , Suínos
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