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1.
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
2.
Genes Immun ; 6(8): 699-706, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16163374

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC(C/T) as well as the FAS-670G>A'-codon214 AC(C/T)' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.


Assuntos
Haplótipos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Fenótipo , Regiões Promotoras Genéticas , Trombocitopenia/patologia , Receptor fas/genética , Afro-Americanos , Alelos , Apoptose , Estudos de Casos e Controles , Códon , Grupo com Ancestrais do Continente Europeu/genética , Proteína Ligante Fas , Genes Reporter , Variação Genética , Humanos , Células Jurkat , Luciferases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/genética , Linhagem , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Fatores de Necrose Tumoral/genética , Estados Unidos , Receptor fas/imunologia
3.
Diabetologia ; 45(1): 134-9, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11845233

RESUMO

AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes mellitus is the result of a T-cell regulated selective destruction of pancreatic beta cells. There is evidence that the apoptosis inducing T-cell effector, Fas ligand (FasL) could be involved in the pathogenesis of Type I diabetes, probably because FasL-mediated apoptosis is important in maintaining peripheral self-tolerance and in down-regulating an immune response. We therefore evaluated the human FasL gene FASL on chromosome 1q23 as a candidate susceptibility gene for Type I diabetes. METHODS: The entire FASL (promoter, exons 1-4 and 3'UTR) was scanned for polymorphisms using single strand conformational polymorphism-heteroduplex analysis and direct sequencing. RESULTS: We identified two novel polymorphisms, a g-C843T and a g-A475T, in a negative regulatory region of the promoter. A Danish Type I diabetes family collection of 1143 subjects comprising 257 families (420 affected and 252 unaffected offspring) was typed for the g-C843T polymorphism and for a FASL microsatellite. Haplotypes were established and data were analysed using the extended transmission disequilibrium test. CONCLUSION/INTERPRETATION: We found no overall evidence for linkage in the presence of association of the FASL polymorphism to Type I diabetes and conclude that FASL does not contribute to the genetic susceptibility to Type I diabetes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Ligação Genética , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Substituição de Aminoácidos , Sequência de Bases , Primers do DNA , Dinamarca , Grupo com Ancestrais do Continente Europeu/genética , Éxons , Proteína Ligante Fas , Feminino , Haplótipos , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Núcleo Familiar , Ácidos Nucleicos Heteroduplexes/genética , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Valores de Referência
4.
Immunogenetics ; 52(1-2): 107-11, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11132145

RESUMO

Type 1 (insulin-dependent) diabetes is a complex trait. The region harboring the ICAM1 gene on 19p13 links to type 1 diabetes, and a growing body of evidence indicates that intercellular adhesion molecule-1 (ICAM-1) could play a role in type 1 diabetes development. Recently, association studies of an ICAM-1 K469E polymorphism in type 1 diabetes populations have reported conflicting results. Hence, we performed a transmission disequilibrium test analysis of the ICAM-1 K469E variations in 253 Danish type 1 diabetes families. Linkage and association was not found between the ICAM-1 K469E variation and type 1 diabetes in Danish patients (P(tdt)> or =0.48), and our data did not indicate an interaction between ICAM1 and IDDM1 in predisposition to type 1 diabetes in Danes (P=0.78). We did not observe significant association with late-onset type 1 diabetes (P(tdt)> or =0.12) or differences in transmission patterns between groups of affected offspring stratified for age at onset (P> or =0.19), as suggested in Japanese patients. Combined analysis of the present and previously reported transmission data comprising 728 affected offspring of Romanian, Finnish, and Danish ancestry suggested association between the ICAM-1 E469 allele and type 1 diabetes (P(tdt)=0.013), but association was not found in the combined Scandinavian material. In conclusion, we found no association of the ICAM-1 K469E polymorphism with type 1 diabetes or its subsets stratified for age at onset and HLA risk in Danish patients. Analysis of ICAM-1 K469E transmissions reported in three populations suggested association to type 1 diabetes, but also demonstrated heterogeneity between populations.


Assuntos
Diabetes Mellitus Tipo 1/genética , Molécula 1 de Adesão Intercelular/genética , Mutação Puntual , Polimorfismo Genético , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade
5.
Diabetologia ; 43(6): 800-8, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10907126

RESUMO

AIMS/HYPOTHESIS: The human Fas gene (FAS) on chromosome 10q24.1 encoding a cell surface receptor involved in apoptosis was evaluated as a candidate susceptibility gene for Type I (insulin-dependent) diabetes mellitus. Apoptosis mediated by Fas is important in maintaining peripheral self-tolerance and in down-regulating the immune response and could have a role in immune-mediated beta-cell destruction. METHODS: We did a molecular scan of the entire human FAS (promoter, exons 1-9 including exon-intron boundaries and the 3'UTR) using single strand conformational polymorphism-heteroduplex analysis. RESULTS: We identified 15 mutations, of which 11 are new. Of these a g-1194A-->T and a g-295Ains give rise to alterations of transcription-factor-binding consensus sequences for c-Myb, SP-1 and NF-kappa B, respectively. A total of 1068 people from a Danish family collection comprising 138 Type I diabetic sib-pair families (289 affected and 121 unaffected offspring) and 103 Type I diabetic parent-offspring multiplex families (103 affected and 112 unaffected offspring) were typed for the three most frequent polymorphisms with high heterozygosity indices and for a FAS microsatellite. Haplotypes were established and data analysed using the extended transmission disequilibrium test, ETDT. CONCLUSION/INTERPRETATION: We found no overall evidence for linkage of the FAS polymorphisms to Type I diabetes. We conclude that it is unlikely that the Fas gene does contribute to genetic susceptibility for Type I diabetes.


Assuntos
Cromossomos Humanos Par 10 , Diabetes Mellitus Tipo 1/genética , Mutação , Receptor fas/genética , Adulto , Criança , Mapeamento Cromossômico , Primers do DNA , Dinamarca , Grupo com Ancestrais do Continente Europeu , Éxons , Feminino , Ligação Genética , Humanos , Masculino , Repetições de Microssatélites , Núcleo Familiar , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples
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