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1.
Scand J Immunol ; 59(6): 582-91, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15182254

RESUMO

CD4 is a candidate gene in autoimmune diseases, including Type 1 diabetes mellitus (T1DM), because the CD4 receptor is crucial for appropriate antigen responses of CD4(+) T cells. We previously found linkage between a CD4-1188(TTTTC)(5-14) promoter polymorphism and T1DM. In the present study, we screened the human CD4 promoter for mutations and identified three frequent single nucleotide polymorphisms (SNPs): CD4-181C/G, CD4-521C/G and CD4-1050T/C. The SNPs are in strong linkage disequilibrium (LD) and association with the CD4-1188(TTTTC)(5-14) alleles, and we observed nine CD4 promoter haplotypes, of which four are frequent. We genotyped the SNPs in 253 Danish T1DM families (1129 individuals) and found evidence for linkage and association of a CD4 (A4(-1188)T(-1050)G(-521)C(-181)) haplotype to T1DM. In reporter studies, we show that (1) the T1DM-associated CD4 haplotype encodes high constitutive promoter activity and (2) the CD4-181G variant encodes higher stimulated promoter activity than the CD4-181C variant. This difference is in part neutralized in the frequently occurring CD4 promoter haplotypes by the more upstream genetic variants. Thus, we report functional impact of a novel CD4-181C/G SNP on stimulated CD4 promoter activity and the identification of a novel CD4 haplotype with high constitutive promoter activity that is linked and associated with T1DM.


Assuntos
Antígenos CD4/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Regiões Promotoras Genéticas , Adolescente , Antígenos CD4/imunologia , Criança , Dinamarca , Diabetes Mellitus Tipo 1/imunologia , Feminino , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Mutação , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética , Sequências de Repetição em Tandem/genética
2.
Diabet Med ; 21(3): 218-22, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15008830

RESUMO

AIMS: To investigate whether the WFS1 gene, the gene for Wolfram syndrome, is a susceptibility gene for more common forms of diabetes in the Danish population. METHODS: One hundred and fifty-two Danish Type 1 diabetes mellitus sib-pair families were genotyped for two microsatellite markers situated within 5 cM of the WFS1 gene and analysed for linkage and association using the sib-TDT. The entire coding region, the 5'UTR and 3'UTR of the WFS1 gene, were screened for mutations by direct sequencing in 29 selected Type 1 diabetes patients. Four of the identified mutations were tested for linkage and association in 255 Danish Type 1 diabetes families (including 103 simplex families). RESULTS: Evidence for linkage to Type 1 diabetes was found as the second most frequent allele of the marker D4S394 were transmitted 137 times (T = 61%) and not transmitted 88 times to affected offspring (Puc = 0.0011). Twelve mutations were found in the coding region and three mutations in the 3'UTR. No evidence for linkage and association to Type 1 diabetes was found testing four of the identified amino acid substitutions. CONCLUSIONS: Evidence of linkage to Type 1 diabetes was observed in the Danish family collection. However, no evidence of linkage and association was observed for any of the analysed polymorphisms, suggesting that other variations must be responsible for the observed evidence of linkage in the region.


Assuntos
Cromossomos Humanos Par 4/genética , Diabetes Mellitus Tipo 1/genética , Ligação Genética/genética , Proteínas de Membrana/genética , Idade de Início , Alelos , Dinamarca , Saúde da Família , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genótipo , Humanos , Repetições de Microssatélites/genética , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único/genética
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.
Diabetes Metab Res Rev ; 17(4): 292-5, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11544613

RESUMO

BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish T1DM-affected sib-pair families and in 240 Sardinian families (229 simplex and 11 sib-pair families). RESULTS: No evidence for association of the two SEL1L markers with T1DM was observed in either the Danish or the Sardinian families. We have also used allelic sharing methods to analyse linkage with T1DM in the IDDM11 region using the same markers and the Danish collection of affected sib-pair families. No evidence of linkage was observed (Z(max)=0.86). CONCLUSION: Although several lines of evidence suggest that SEL1L might be a candidate for IDDM11-conferred susceptibility to T1DM the present study does not support this hypothesis.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Proteínas/genética , Alelos , Cromossomos Humanos Par 14 , Dinamarca , Ligação Genética , Genótipo , Humanos , Itália , Repetições de Microssatélites
6.
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
7.
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
8.
Genes Immun ; 1(3): 170-84, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11196709

RESUMO

For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. In this review, we critically evaluate the evidence for pathogenetical involvement of CTLA-4 in the different autoimmune diseases with focus on the possible role of genetic variation of the CTLA4 locus.


Assuntos
Antígenos de Diferenciação/genética , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Imunoconjugados , Abatacepte , Doença de Addison/genética , Doença de Addison/imunologia , Animais , Antígenos CD/genética , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Antígeno B7-1/genética , Antígeno B7-2 , Antígenos CD28/genética , Antígeno CTLA-4 , Doença Celíaca/genética , Doença Celíaca/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/genética , Camundongos , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Mutação , Miastenia Gravis/genética , Miastenia Gravis/imunologia , Polimorfismo Genético , Ratos , Doenças da Glândula Tireoide/genética , Doenças da Glândula Tireoide/imunologia , Vitiligo/genética , Vitiligo/imunologia
9.
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
10.
Autoimmunity ; 31(1): 35-42, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10593567

RESUMO

Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic susceptibility. The major genetic component (IDDM1) resides within the HLA region, but several non-HLA loci have been implicated in the genetic susceptibility. In the present study, we have analysed two such loci, IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type 1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was observed in any of the two studied data sets. However, when the present data were combined with previously published data, they strengthened the evidence of linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02, and 0.007, respectively) using transmission disequilibrium testing (TDT) and the Tsp version of the TDT. Importantly, random transmission of all tested alleles was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk and non-high risk genotypes) in the Danish families did not reveal heterogeneity at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus in the Danish population. In addition, we found support for evidence of linkage and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to type 1 diabetes, however, further studies are needed to substantiate this observation.


Assuntos
Antígenos de Diferenciação/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Imunoconjugados , Abatacepte , Alelos , Antígenos CD , Antígeno CTLA-4 , Grupo com Ancestrais do Continente Europeu/genética , Antígenos HLA/genética , Humanos , Desequilíbrio de Ligação , Repetições de Microssatélites
11.
Hum Mutat ; 14(1): 67-70, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10447260

RESUMO

Recent genome screening studies have identified novel regions of possible interest for susceptibility to type 1 diabetes. One of these is a 30-35 cM region mapping to 16q22-q24 (D16S515-D16S520), where also the gene encoding NAD(P)H: quinone oxidoreductase (NQO1) maps. Data has suggested association of a polymorphism (P187S) in the NQO1 gene and type 1 diabetes. NQO1 is involved in protection against oxidative stress, which is likely to be involved in beta-cell destruction. By use of the transmission disequilibrium test (TDT), we analyzed the P187S polymorphism for association to type 1 diabetes in a population-based sample of 247 Danish nuclear type 1 diabetic families. Random transmission patterns were observed to all affected offspring (p(tdt) = 0.82), to index cases (P(tdt) = 0.77), as well as to unaffected offspring (P(tdt) = 0.93). Hence, the NQO1 polymorphism is not likely to be an etiological mutation underlying the reported linkage of the 16q22-q24 region.


Assuntos
Diabetes Mellitus Tipo 1/genética , Ligação Genética , NAD(P)H Desidrogenase (Quinona)/genética , Polimorfismo Genético , Cromossomos Humanos Par 16 , Dinamarca , Diabetes Mellitus Tipo 1/enzimologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Desequilíbrio de Ligação , Masculino
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