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

There is substantial interest in the identification of genes underlying susceptibility to complex human diseases because of the potential utility of such genes in disease prediction or therapy. Type 1 diabetes is an example of one such disorder and is presumed to arise from the effect of multiple genes and environmental factors. One identified locus has a major effect on type 1 diabetes susceptibility (IDDM1), whereas other loci have significant, yet small, individual effects (IDDM2, IDDM15). It is unclear whether susceptibility for type 1 diabetes arises because of the effects of loci acting independently or whether there are important interactions between loci. Although genetic tools are continuing to be developed to enable examination of candidate regions, the means to identify and narrow "true" susceptibility regions continues to be limited by the lack of statistical power resulting from inadequately sized collections of families. This report provides an evaluation of the approaches for identification of regions harboring type 1 diabetes genes, methods to identify the gene regions that interact to define the risk for type 1 diabetes, and efforts to fine-map the variants responsible.
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PMID:Challenges and strategies for investigating the genetic complexity of common human diseases. 1247 65

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C>T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 C>T SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 C>T and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.
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PMID:Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene. 1455 99

Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-gamma), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10(*)R2, IL-4(*)C, VDR(*)C and IGF-I(*)wt was found to be transmitted more frequently than expected (67%, P(c)=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.
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PMID:Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes. 1473 47

Type 1 diabetes (T1D) mellitus is a multifactorial autoimmune disease where more than 90% of insulin-producing pancreatic beta cells are destroyed before the clinical manifestations, warranting a need to identify the children predisposed to get the disease. Of the 20 genomic intervals implicated for the risk to develop T1D, the major histocompatibility complex (MHC) region on chromosome 6p21.31 (IDDM1) has been the major contributor, followed by 5' regulatory region of the insulin (INS) gene on chromosome 11p15.5 (IDDM2). MHC has a role in antigen presentation and IDDM2 has been shown to have a role in transcription of insulin in the thymus. Hence, alleles of human leukocyte antigen (HLA)-DRB1, DQB1, and insulin-linked variable number of tandem repeats (INS-VNTR) were studied in 110 T1D patients and 112 healthy controls using polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes (PCR-SSOP) and PCR restriction fragment length polymorphism (PCR-RFLP), respectively. HLA-DRB1*0301 was significantly increased in the T1D patients along with associated DQB1*0201 followed by DRB1*0401 and DRB1*0405. DRB1*0701 was observed to be the most protective allele followed by DRB1*0403 and DRB1*0404. Although DQB1*0302 which is associated with both the protective and susceptible DR4 alleles was not significantly increased, heterozygous DQB1*0201, *0302 was significantly increased in the TID patients. Because INS-VNTR class I homozygosity was also significantly increased in the patients, simultaneous presence of DRB1*0301 along with homozygous INS-VNTR class I, gave a relative risk (RR) of 70.81. However, a similar analysis of DQB1*0201 and *0302 along with INS-VNTR alleles did not give such high RRs. Thus, the two independently assorting alleles at two loci i.e., DRB1*0301 and INS-VNTR class I, on two different chromosomes may have the potential to predict a prediabetic in North India.
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PMID:Molecular basis of predisposition to develop type 1 diabetes mellitus in North Indians. 1524 69

Although autoimmune diseases can be initiated by immunization with a single antigen, it is not clear whether a single self antigen is essential for the initiation and, perhaps, the perpetuation of spontaneous autoimmunity. Some studies have suggested that insulin may represent an essential autoantigen in type 1 diabetes. Here we show that unlike tolerance to glutamic acid decarboxylase, tolerance to transgenically overexpressed preproinsulin 2 substantially reduced the onset and severity of type 1 diabetes in nonobese diabetic mice. However, some mice still developed type 1 diabetes, suggesting that insulin is a key, but not absolutely essential, autoantigen. The results are consistent with the idea that the human IDDM2 locus controls susceptibility to type 1 diabetes by regulating intrathymic preproinsulin expression.
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PMID:Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. 1537 58

Type I diabetes is a complex disease in which multiple susceptibility loci have been implicated by whole genome scans. IDDM8, a susceptibility locus, is located on chromosome 6q27, however the specific susceptibility gene has yet to be identified. We have examined five potential candidate genes using 36 genetic markers, spanning 360kb located near the chromosome 6q27 terminus in 478 families for diabetes association. No associations with type I diabetes susceptibility were detected with the strength previously observed for IDDM1 or IDDM2. However, a novel CAG/CAA polymorphism was detected in exon 3 of the TATA box-binding protein gene, which shows preliminary evidence of association with diabetes susceptibility (p<0.05).
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PMID:Association of a CAG/CAA repeat sequence in the TBP gene with type I diabetes. 1538 Oct 80

There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.
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PMID:Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. 1556 61

Type 1 diabetes is associated with autoimmune responses against insulin, with insulin autoantibodies (IAA) being a hallmark of the disease. Genetic susceptibility to type 1 diabetes is polygenic and includes the INS VNTR-IDDM2 locus, which has been shown to regulate the expression of insulin in the pancreas and thymus. In order to determine whether insulin autoimmunity could be attributed to a genetic susceptibility conferred by the INS-VNTR (IDDM2) locus, we studied the frequency of INS-VNTR alleles and the presence of IAA in 90 patients with new-onset type 1 diabetes. IAA were detected in 49 of 67 class I/I individuals and 19 of 23 class III/X patients, indicating that there is no association between the INS VNTR-IDDM2-susceptible allele and humoral autoimmunity against insulin. This finding does not support the hypothesis of an allele-specific tolerance induction that could determine susceptibility toward autoimmunity against the insulin protein and subsequently the development of type 1 diabetes.
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PMID:No association of INS-VNTR genotype and IAA autoantibodies. 1569 5

Both genetic and nongenetic factors contribute to the development of type 1 diabetes. Many investigations, including prospective studies of high-risk children, have implicated virus infections as predisposing environmental agents. We previously reported that basal activity of the key antiviral enzyme 2'5'-oligoadenylate synthetase (2'5'AS) was significantly elevated in type 1 diabetic patients compared with healthy control subjects. Recently, we showed that an A/G splice site single nucleotide polymorphism (SNP) in the OAS1 gene encoding 2'5'AS is strongly associated with basal 2'5'AS activity. Basal enzyme activity was highest in individuals with GG genotype and lowest in those with AA genotype. In the present study, we genotyped 835 type 1 diabetic and 401 healthy siblings at the OAS1 splice site polymorphism and (for comparison) at an A/C SNP of the insulin (IDDM2) locus. Results showed that OAS1 GG and GA were significantly increased in diabetic compared with healthy siblings (P = 0.0023). The strength of association was similar to that at IDDM2, where, as expected, the C/C (variable number tandem repeat class I homozygote) genotype was increased in affected compared with healthy siblings (P = 0.0025). The results suggest that host genetic response to virus infection could influence susceptibility to type 1 diabetes.
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PMID:OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. 1585 50

It is well established that the polymorphisms at the 5' of the insulin gene (IDDM2) confers susceptibility to type 1 diabetes, probably by modifying the level of insulin expression in the thymus that in turn influences immunological tolerance to insulin as self-antigen. AIRE is a transcription regulator which controls the expression of many peripheral antigens within the thymus, among them insulin. Results presented here confirm that insulin gene copies from both parental chromosomes are expressed in human thymus and that IDDM2 class III protective alleles are indeed associated with a higher level of insulin message expression. However, differences in insulin mRNA expression among different thymi were far wider than those determined by the class I and class III insulin gene alleles and maintained a clear correlation with AIRE expression. These results confirm the effect of IDDM2 alleles on insulin expression in the thymus, but suggest that the levels of AIRE may exert a stronger influence than IDDM2 alleles themselves.
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PMID:Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus. 1624 24


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