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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 12 (IL-12) has been implicated in the pathogenesis of type 1 diabetes in the non-obese diabetic (NOD) mouse. Following this lead, a new locus associated with human type 1 diabetes, IDDM18, has been identified near the gene encoding the p40 subunit of interleukin 12 (IL12B). This finding has potential implications for the prediction of at-risk individuals and, perhaps, for the implementation of prevention strategies relevant to several autoimmune diseases.
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PMID:Interleukin 12 and autoimmune diabetes. 1117 94

Type 1 diabetes (T1D; or insulin-dependent diabetes mellitus, IDDM) is an autoimmune disease with both genetic and environmental components. In addition to the human leukocyte antigen (HLA) complex, the single major genetic contributor of susceptibility, an unknown number of other unidentified genes are required to mediate disease. Although many loci conferring susceptibility to T1D have been mapped, their identification has proven problematic due to the complex nature of this disease. Our strategy for finding T1D susceptibility genes has been to test for human homologues of loci implicated in diabetes-prone NOD (non-obese diabetic) mice, together with application of biologically relevant stratification methods. We report here a new susceptibility locus, IDDM18, located near the interleukin-12 (IL-12)p40 gene, IL12B. Significant bias in transmission of IL12B alleles was observed in affected sibpairs and was confirmed in an independent cohort of simplex families. A single base change in the 3' UTR showed strong linkage disequilibrium with the T1D susceptibility locus. The IL12B 3' UTR alleles showed different levels of expression in cell lines. Variation in IL-12p40 production may influence T-cell responses crucial for either mediating or protecting against this and other autoimmune diseases.
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PMID:Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. 1117 71

Coeliac disease (CD) is a chronic inflammatory disorder where dietary gluten is not tolerated. In the lesion there are gluten reactive T cells predominantly secreting gamma-interferon. Both HLA and non-HLA genes contribute to CD susceptibility. Interleukin-12 (IL-12) regulates gamma-interferon production. The IL12B gene is located in a region (5q31.1-33.1) where there is evidence for linkage with CD. Allele 1 of an IL12B 3'UTR single-nucleotide polymorphism leads to increased expression of IL-12, and was recently implicated in susceptibility for type 1 diabetes (T1D). We found no evidence for association of allele 1 to CD by the transmission/disequilibrium test or case-control approach. No increased frequency was observed in patients belonging to families where the disease was linked to markers on chromosome 5q. Unlike T1D, allele 1 does not appear to confer susceptibility to CD.
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PMID:The IL12B gene does not confer susceptibility to coeliac disease. 1197 87

Type 1 diabetes mellitus (T1D) results from decreased insulin production. Its clinical expression is the result of an array of genetic and environmental factors. The IL12B gene could be one of the loci implicated in the genetic susceptibility of T1D. Thus, this genetic predisposition could be modulated by dietary factors. However, there is no consistency among populations in relation to relevance of this locus as a candidate gene for T1D.
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PMID:Is IL12B a potential genetic target for the prevention of type 1 diabetes through dietary intervention? 1207 18

Type 1 diabetes is an autoimmune disease with a complex polygenic inheritance. Until recently, only three susceptibility genes had been reproducibly identified, namely HLA, INS-VNTR, and CTLA4. During the past 7 years, a number of new putative susceptibility genes have been isolated from both human and animal models of the disease. We present eight genes implicated in type 1 diabetes etiology and discuss them in relation to the pathogenesis of the disease: VDR, IL6, IL12B, AIRE, FOXP3, B2m, Cblb, and Lyp/Ian4l1.
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PMID:New autoimmune genes and the pathogenesis of type 1 diabetes. 1503 74

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.
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PMID:A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. 1567 37

Carriage of a polymorphism in the 3'untranslated region of the IL12B gene encoding IL-12p40 was investigated in subjects with type 1 diabetes mellitus stratified by age at diagnosis (n = 648) and compared with a population-based control cohort (n = 246) residing in Western Australia. DNA samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism or pyrosequencing. The C allele was more common in patients diagnosed after age 16 years than in controls (29% vs 17%, OR = 2.0, 95% CI = 1.4-2.7, p = 0.00003) or than in patients diagnosed when younger age 16 years (29% vs 22%, OR = 1.4, 95% CI = 1.1-1.9, p = 0.01). This reflected increases in homozygous and heterozygous carriage of the C allele. Heterozygosity was associated with a delayed disease in the late-onset diabetics (p = 0.005; Student's t-test). The effects of IL12B 3'untranslated region alleles on type 1 diabetes mellitus may reflect different levels of p40 available to form p40 homodimer, IL-12 (p35p40), and IL-23 (p19p40).
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PMID:Alleles of the IL12B 3'UTR associate with late onset of type 1 diabetes. 1560 69

Several polymorphisms in regions where Th1 cytokines (IL12B and IFNG genes) are located were analyzed in 303 Spanish subjects with type 1 diabetes and compared with a control cohort (n = 548). Both groups comprised residents of the Madrid area. The haplotype frequencies were estimated by the expectation-maximization algorithm, and p values were corrected by the number of haplotypes taken into account in the study. Two haplotypes were significantly associated with the disease, one in the IL12B region (D5S2038*8/D5S1352*2/SNP1188C; OR = 3.01, p(c) = 0.0255) and another involved the IFNGgene (D12S313*9/IFNG*1; OR = 1.58, p(c) = 0.0217). Furthermore, a protective IL12B haplotype was found (D5S2038*4/D5S1352*1/SNP1188A; OR = 0.40, p(c) = 0.0405). No association was found for any of IL12B and IFNG markers individually.
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PMID:Th1 cytokine polymorphisms in spanish patients with type 1 diabetes. 1621 74

The evidence that there is clinical heterogeneity of type 1 diabetes is reviewed and the implications for genetic studies are discussed. In the past year, genome-wide linkage analysis of 1435 multiplex families was reported. Additionally, confirmed evidence for association of specific markers at two loci (PTPN22, OAS1) as well as failure to replicate three others (IL12B, SUMO4, PAX4) is discussed. Some common themes are identified and suggestions for improvements are made. We look forward to the results from genome-wide association studies.
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PMID:Genetic epidemiology of type 1 diabetes. 1654 25

As part of its efforts to identify genes affecting the risk of type I diabetes (T1D), the Type I Diabetes Genetics Consortium commissioned an extensive survey of variants associated with genes reported earlier to have an association with disease susceptibility. In this report, we present the analysis of a set of single-nucleotide polymorphisms (SNPs) within and flanking the IL12B gene, which encodes the p40 subunit of the cytokines interleukin (IL)-12 and IL-23. No SNP showed individually significant association in the population as a whole. Nevertheless, subjects stratified according to genotype at the earlier reported SNP in the IL12B 3'UTR, rs3212227, confirmed small, but significant, differences in age of disease onset with a relative hazard=0.88 (P=0.005). The protective effect of rs3212227 allele 2 was gender specific (P=0.004 overall and P=0.0003 when unaffected siblings were considered). Among females, the 2.2 genotype was more protective, with relative hazard=0.75. We conclude that while there was no major effect of IL12B polymorphisms on T1D susceptibility in the entire study group, they have an impact on a subset of at-risk individuals.
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PMID:Evaluation of IL12B as a candidate type I diabetes susceptibility gene using data from the Type I Diabetes Genetics Consortium. 1995 4


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