UMLS:C0011854 - FACTA Search

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

Type I Insulin-Dependent Diabetes Mellitus (IDDM) is an autoimmune disease characterised by the destruction of pancreatic Beta cells. There is an evidence for a contribution of genetic factors to the development of the disease and it is widely documented that HLA antigens contribute to the disease susceptibility. HLA-DR3 and HLA-DR4 associations have been firstly described in Caucasian. Recent studies at the gene level have elucidated this HLA association more precisely, pointing out the prominent role of HLA-DQ locus genes. The hypothesis has been proposed that some critical amino-acid at position 57 of DQ Beta chain and at position 52 of DQ Alpha chain both contribute to disease susceptibility. According to the functional role of HLA class II molecules, these particular residues may affect the antigen binding and T cell recognition and therefore contribute to the triggering of the pathological auto-immune response.
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PMID:[Genetic susceptibility of insulin-dependent diabetes]. 129 34

The major histocompatibility complex (MHC) contains multiple and diverse genes which may be relevant to the induction and regulation of autoimmune responses in insulin dependent diabetes mellitus (IDDM). In addition to HLA class I and II, the possible candidates include TNF, C4, and several other poorly defined polymorphic genes in the central MHC region. This study describes two approaches which take advantage of the fact that the relevant genes are carried by highly conserved ancestral haplotypes such as 8.1 (HLA-B8, TNFS, C4AQ0, C4B1, DR3, DQ2). First, three "diabetogenic" haplotypes (two Caucasoid and one Mongoloid) have been compared and it has been shown that all three share a rare allele of BAT3 as well as sharing DR3, DQ2. In 43 sequential patients with IDDM the cross product ratio for BAT3S was 4.8 (p less than 0.01) and 6.9 for HLA-B8 plus BAT3S (p less than 0.001). Second, partial or recombinant ancestral haplotypes with either HLA class I (HLA-B8) or II (HLA-DR3, DQ2) alleles were identified. Third, using haplotypic polymorphisms such as the one in BAT3, we have shown that all the patients carrying recombinants of the 8.1 ancestral haplotype share the central region adjacent to HLA-B. These findings suggest that both HLA and non-HLA genes are involved in conferring susceptibility to IDDM, and that the region between HLA-B and BAT3 contains some of the relevant genes. By contrast, similar approaches suggest that protective genes map to the HLA class II region.
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PMID:Ancestral haplotypes reveal the role of the central MHC in the immunogenetics of IDDM. 135 98

Insulin-dependent diabetes mellitus (IDDM) in Caucasians is strongly associated with HLA-DR3-DQ2 and DR4-DQ8. In order to investigate the HLA class II associations with IDDM in Algerians, we have used polymerase chain reaction (PCR) and sequence specific oligonucleotide analysis (SSO) to identify DQA1, DQB1, and DRB1 alleles, haplotypes and genotypes in 50 unrelated IDDM patients and 46 controls from a homogeneous population in Western Algeria. Both DRB1*0301-DQA1*0501-DQB1*0201 (DR3-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) haplotypes were found at increased frequencies among the patients compared to controls (45% vs. 13%, RR = 5.5, Pc < 10(-5) and 37% vs. 4%, RR = 12.9, Pc < 10(-4), respectively). Among the latter, in contrast to other Caucasian populations, only DRB1*0405-DQA1*0301-DQB1*0302 was significantly increased in the Algerian patients (25% vs. 1% in controls, RR = 30.3, Pc < 10(-3). Accordingly, the highest risk of disease was observed in DRB1*0301-DQA1*0501-DQB1*0201/DRB1*0405-DQA1+ ++*0301-DQB1*0302 heterozygotes (34% in patients vs. 0% in controls; RR = 49; Pc < 10(-3). This observation and its comparison with DR-DQ haplotypes in other ethnic groups suggest that the DRB1*0405 allele which encodes an Asp57-negative beta chain may contribute to IDDM susceptibility in a similar way as Asp57-negative DQ beta chains.
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PMID:The HLA-DRB1*0405 haplotype is most strongly associated with IDDM in Algerians. 147 90

Eighty unrelated diabetic children, seventy healthy controls and hundred and ten affected and unaffected first-degree relatives of twenty multiplex families were investigated by restriction fragment length polymorphism analysis of HLA class II genes using five probe/enzyme systems: DRB and DQB/Taq I, DRB and DQB/EcoRI and DQB/BamHI according to standard procedures described in the 10th Histocompatibility Workshop protocol. Comparison between the unrelated diabetic patients and the controls confirmed the positive association of type 1 diabetes with DR3(w17)DQw2 Dw24 or Dw25 and DR4DQw8 and the negative association with DR2(w15)DQw6, DR4DQw7 and DR7DQw2 haplotypes. In multiplex families, similar allele associations were found and the distinction between haplotypes present in diabetic patients and those that segregated to healthy family members allowed to observe striking differences between the "affected" and "unaffected" haplotypes, particularly for the subtypes of DR3(w17) DQw2, DR4DQw3 and DR2DQw1 haplotypes. Heterozygous siblings who carried both DR3DQw2 and DR4DQw8 subtypes disclosed a highly increased risk and more than 80% of DR3/DR4 affected siblings received a paternal DR4DQw8 together with a maternal DR3DQw2. These observations indicate that several genetic aspects influence susceptibility to type 1 diabetes: 1) some particular HLA class II subsets; 2) the parental origin of the predisposing genes; 3) the synergistic effect of both haplotypes, in particular DR3DQw2 and DR4DQw8. These results may help to better specify susceptibility markers for risk prediction in siblings.
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PMID:DNA polymorphism analysis of HLA class II genes in unrelated children and in first-degree relatives with type I diabetes. 168 61

HLA class II associations with IDDM in populations of non-Caucasoid origin can provide important insights into the nature of the HLA and disease association. Firstly, HLA class II alleles that are rare in Caucasoids but common in other populations can be assessed for their contributory role in IDDM. Secondly, the different HLA class II gene linkage arrangements in different populations can help map the IDDM susceptibility determinants. This chapter reviews studies of HLA class II associations with IDDM in Asian Indians, Chinese, Japanese, Africans and black Americans. Most of these studies have been based on HLA-DR serology. However, DNA analyses, based on restriction fragment length polymorphism, sequence specific oligonucleotide hybridizations of polymerase chain reaction products and DNA sequencing, have made clear the identity of genes contributing to susceptibility or resistance to IDDM in populations of non-Caucasoid origin. DNA sequence analysis of the variable regions of the HLA-DQA, DQB and DRB genes has revealed at least eight alleles at HLA-DQA, 13 at HLA-DQB and 34 at HLA-DRB1. This chapter correlates HLA-DR and DQ allelic diversity with inherited predisposition to IDDM on a global basis. IDDM is strongly associated with the serological specificities of HLA-DQ, rather than with particular amino acid substitutions in class II alleles. DQw8 has a high risk for IDDM, DQw4, DQw5 and DQw9 have a lesser risk, while DQw6 and DQw7 are protective in IDDM. DQw2 is permissive for IDDM, depending on the presence of other HLA class II alleles. Increased heterozygosity at HLA is observed in Oriental patients, as it is in Caucasoid IDDM patients. The nature of this synergism is examined in terms of possible interactive effects between DQA and DQB alleles or DRB and DQB alleles; both effects could be operating. The conclusion from this genetic analysis is that molecular mimicry at HLA-DQ, with either foreign or autoantigens, may be an important mechanism in IDDM. Additionally, the anomalous role of DQw2 in IDDM suggests that a further mechanism, such as T cell activation, may control the ability to mount an immune response against autoantigens. Further studies, possibly with transfectant cell lines, are necessary to clarify the functional role of HLA class II genes in IDDM.
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PMID:Cross-ethnic group comparisons of HLA class II alleles and insulin dependent diabetes mellitus. 189 68

The analysis of HLA class II sequence variation in IDDM patients and controls, made possible by the PCR, has revealed that specific alleles are associated with IDDM. The HLA-DQ beta chain appears to play a role in determining genetic susceptibility and resistance, although polymorphisms in the DRB1, the DQ alpha, and the DP beta chain may also contribute. Although there is a correlation between susceptibility and the charge of DQ beta residue 57, the complex genetic epidemiology of IDDM cannot be accounted for by polymorphism at this position. As we have discussed previously (Horn et al, 1988a, 1988b; Erlich et al, 1990b), there are no unique class II sequences associated with IDDM, consistent with the view that 'normal' class II alleles confer susceptibility. Given the estimates of concordance of under 50% for monozygotic twins and approximately 15% (Tattersall and Pyke, 1972; Thomson, 1988) for HLA-identical sibs--it is not surprising that some unaffected individuals contain putative susceptibility alleles. Perhaps some environmental 'triggering' agent, such as viral infection, is required for the disease to develop in susceptible individuals. Other non-MHC-linked genes which contribute to susceptibility may account for the difference in concordance rates for monozygotic twins and for HLA-identical sibs. In the NOD (non-obese diabetic) mouse and the BB rat models for IDDM, non-MHC susceptibility loci have been identified and mapped (Colle et al, 1981; Hattori et al, 1986) but, in humans, the analysis of non-MHC candidate loci (i.e. the T cell receptor) has, thus far, failed to reveal any other susceptibility loci. In general, the HLA-linked genetic susceptibility to IDDM, as well as to other autoimmune diseases, appears to be associated with specific combinations of class II epitopes (e.g. alleles, haplotypes or genotypes) rather than with specific individual residues or epitopes. Understanding the role of these predisposing sequences will require structural analysis of the class II molecules as well as in vitro and in vivo functional studies of interactions with putative autoantigens and T cell receptors. In the meantime, DNA typing offers the potential for identifying individuals at high risk. These susceptible individuals could be monitored by immunological (e.g. anti-islet cell antibody) or by metabolic tests to detect the preclinical phase of IDDM.
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PMID:HLA class II sequences and genetic susceptibility to insulin dependent diabetes mellitus. 190 60

The main principles of this hypothesis are very general: (i) signal-detection from background noise is one central issue in electronics; (ii) an important source of misunderstanding at different levels of communication is the fact that a given signal may have different meanings in different contexts; (iii) the unique role of chance in developmental biology is generally appreciated (37). In AIDS the basic defect would be the human specific inability to distinguish between the amino acid sequence of neuroleukin and peptides derived from the gp120 envelope protein of HIV, resulting in a slowly progressing failure of the CD4+ T cell-mediated immunity. In IDDM the postulated HLA class II-dependent hypersensitivity to immunological noise could predispose to random contacts between cells with a different signalling language. In the ensuing dialogue neuroleukin secreted by T cells would imply a continuous demand for insulin secretion to pancreatic beta cells resulting in diabetes. This hypothesis does not contradict with the provocative ideas proposed by Duesberg concerning the relationships between HIV and AIDS (24) and the known data on the genesis of IDDM.
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PMID:Are syntax errors due to the amino acid sequence of neuroleukin involved in the pathogenesis of the acquired immunodeficiency syndrome (AIDS) and insulin dependent diabetes mellitus (IDDM)? 204 84

Associations between a large number of diseases and markers within the major histocompatibility complex (MHC) have been described. In particular, susceptibility to several autoimmune disorders, including type I diabetes mellitus and rheumatoid arthritis, is linked to genes within the MHC and strong population associations are demonstrable between certain HLA class II alleles and these conditions. Genetic mapping of HLA susceptibility loci has traditionally relied on the use of phenotypic markers defined by alloantisera, cellular typing reagents and biochemical analysis of histocompatibility antigens. Polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) typing combines the ability to define the finest of HLA specificities, by analysis of the corresponding DNA sequences, with the possibility of study large populations of normal and affected individuals. The applications of this technology to characterizing precisely the MHC loci associated with susceptibility to autoimmune diseases such as rheumatoid arthritis, type I diabetes mellitus, coeliac disease and pemphigus vulgaris are reviewed here.
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PMID:PCR-SSO typing in HLA-disease association studies. 206 41

Family and population studies indicate that predisposition to insulin-dependent (type I) diabetes mellitus (IDDM) is polygenic. It has been shown that the absence of the aspartic acid in position 57 (Asp57) of the DQ beta chain is positively correlated to IDDM. However, Asp57-negative haplotypes do not always confer susceptibility and conversely, some Asp57-positive haplotypes seem to be disease associated. It has been suggested that other HLA class II sequences, probably belonging to the HLA DQA1 gene, confer susceptibility to IDDM. This report, based on extensive oligonucleotide dot blot hybridization of PCR-amplified DQA1 and DQB1 genes, reinforces the importance of the Asp57-negative DQ beta chain, but also introduces the possibility that a DQ alpha chain bearing an arginine in position 52 (Arg52) confers susceptibility to IDDM. A molecular model of susceptibility to IDDM is proposed. This model strongly suggests that the disease susceptibility correlates quantitatively with the expression at the cell surface of a heterodimer, composed of a DQ alpha-chain bearing an Arg52 and a DQ beta chain lacking an Asp57. In view of the respective positions of the two residues and their charge, we might anticipate that both residues DQ beta Asp57 and DQ alpha Arg52 are critical for modulation of susceptibility, presumably via viral-antigenic peptide and/or autoantigen presentation.
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PMID:A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. 231 83

Our understanding of HLA class II polymorphism has undergone a rapid evolution in the last few years. As in so many areas of modern biology, this progress has depended largely on the application of recombinant DNA techniques to the study of this gene family. In particular, the recent development of methods of gene amplification by means of the polymerase chain reaction has allowed for the rapid assessment of polymorphism in the human population. In addition, the elucidation by x-ray crystallographic analysis of the three-dimensional structure of an HLA molecule has been a major step. These areas of progress have now begun to converge to allow a more detailed approach to the problem of class II polymorphism and disease susceptibility. As discussed in this review, the data so far indicate that a few amino acid substitutions in class II molecules may exert a critical influence on susceptibility to autoimmune diseases such as RA and IDDM. The mechanism by which these class II polymorphisms predispose to autoimmune disease is still unknown. It is tempting to speculate that differences in the binding affinity of HLA molecules for autoantigens might be involved; however, as yet no specific autoantigen has been identified for either RA or IDDM. Intriguingly, sequence similarities have been observed between some viral proteins and class II molecules, raising the possibility that these infectious agents might induce autoimmunity by "molecular mimicry." Examples include the human cytomegalovirus protein, IE2 as well as the Epstein Barr virus gp110 protein. Other possible mechanisms involve more complex immunoregulatory effects, such as the absence of suppressor functions that appear to be under the influence of the HLA genes. To some extent, the persistent ignorance about the cause of autoimmunity reflects a general lack of knowledge concerning exactly how HLA polymorphisms exert immunoregulatory effects. For example, in addition to influencing antigen presentation, MHC molecules also affect the overall T cell repertoire during thymic selection. The relative importance of HLA class II polymorphism in exerting immunoregulatory effects by means of thymic selection of the T cell repertoire is unknown. For autoimmune diseases such as RA and IDDM, there is a need to identify a specific functional abnormality that is causing the disease before the etiological significance of the emerging associations with class II polymorphisms become clear.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:HLA class II polymorphism: implications for genetic susceptibility to autoimmune disease. 266 47

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