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

The specific genes causing type 1 diabetes susceptibility in any species are unknown. Serological HLA studies have shown susceptibility to type 1 diabetes is linked to HLA DR3 and DR4 allels, whereas DR2 and DR5 alleles contain protective elements. DR4 chromosomes can be divided into diabetes prone or resistant by restriction fragment length polymorphism analyses with cDNA probes for DQ beta-gene. No type 1 diabetes-specific environmental factors have been revealed to be convincingly implicated in human type 1 diabetes. Congenital rubella, by its lasting influence on T cells creates susceptibility to many organ-specific autoimmune diseases. Certain dietary proteins shown in BB rats as well as hyperglycemia during the prenatal period increase the later incidence of type 1 diabetes. Human type 1 diabetes results from a progressive probably autoimmune loss of the pancreatic beta cells. The immunologic hallmarks of type 1 diabetes is the lymphocytic infiltration of pancreatic islets, the hyperexpression of class I MHC on all islet cells and the abarrent class II MHC expression on beta cells within inflamed islets, the increased frequency of activated T cells in islet and circulation. It is generally accepted that cellular immunity plays the major role in the pathogenesis of type 1 diabetes. The heightened autoimmune reactivity being detectable during the preclinical period, lasting months to years, has been proved by antibodies directed against cytoplasmic islet cell antigens (ICA), beta cell surface antigens (ICSA), insulin (IAA), and with a lower frequency against non-islet cell antigens. The presence of IgG insulin autoantibodies and complement fixing ICA confers increased risk for future type 1 diabetes development in genetically predisposed individuals than the presence of either marker alone. For ICSA a more specific and quantitative assay is needed. 90% of children developing type 1 diabetes were detected positive for ICA and/or IAA. By the time of clinical onset if type 1 diabetes some 90% of the insulin secretory beta cell mass has already been destroyed. For this reason, new approaches are needed to address the causes of diabetes and not just the consequences. The development of insulin-dependent diabetes may be reversible, or even preventable by early detection coupled with the judicious use of immunotherapy.
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PMID:Immunological disorders of type 1 diabetes mellitus. 268 94

HLA class II genes have been implicated in susceptibility to a number of diseases. We have previously identified two allelic variants of DQw3 and have shown that DR4-DQ beta 3.2 haplotypes are associated with increased risk of IDDM whereas DR4-DQ beta 3.1 haplotypes are not. DR5 and DR8 DQw3+ individuals are exclusively DQ beta 3.1 and share numerous restriction sites within the DQ beta genes with DR4-DQ beta 3.1 individuals. In order to compare the DQ beta 3.1 genes associated with different haplotypes, we have sequenced coding and noncoding regions of the DQ beta genes from a DR4-DQ beta 3.1 HTC (ER) and a DR8-DQ beta 3.1 HTC (LUY). LUY and ER DQ beta genes share nucleotide substitutions in both the beta 1 and beta 2 exons, yielding six amino acid replacements distinguishing them from DQ beta 3.2. In the noncoding regions as well, LUY and ER share nucleotide substitutions distinguishing their DQ beta 3.1 genes from DQ beta 3.2. These data support the concept that the DQ beta 3.1 allele was introduced onto different backgrounds via homologous recombination.
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PMID:Molecular analysis of DQ beta 3.1 genes. 289 47

From the study of HLA, A, B, C, DR, Bf and C4A, C4B alleles in 287 insulin-dependent diabetes mellitus patients and 108 controls, comparisons were made between 424 diabetic and 216 normal extended haplotypes. In the "cis" situation (haplotype), the highest relative risks (RR) for IDDM were borne by multiloci allelic associations, mainly DR/complement alleles, rather than by DR3 or DR4 considered alone. Susceptibility was strongly associated with two extended haplotypes (Aw30, Cw5, B18, C4BQ0, C4A3, BfF1, DR3 and A2, Cw3, B15, C4Bx, C4A3, BfS, DR4) or their smaller segments. Two haplotypes, S31 associated with DR2 or DR5 and F31 associated with DRw6 or DR7 had a protective effect. In the "trans" situation (opposite haplotype) the large excess of DR3/DR4 heterozygotes was not the only distortion observed. An excess of DR1 (57%) and of C4BQ0 (40%) was noted among non DR3, non DR4 haplotypes in diabetics compared to normal individuals (26% and 23%, respectively, P less than 0.01, 0.05). Homozygotes for DR3 or DR4 were not increased, and other homozygotes were decreased compared to controls. The protective antigens HLA DR2, DR5 and DR7 seemed not to be distributed randomly: their putative protective effect was not observed in the case of combination with DR1 or a B18, DR3 haplotype. DR2 was never found homozygous or combined with DR5. These results suggest that susceptibility to IDDM is generated by both cis and trans interactions between genes or gene products of the HLA region.
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PMID:Study of cis and trans interactions between extended HLA-haplotypes in insulin-dependent diabetes. 340 91

To investigate the possible coinheritance of autoimmune diseases that are associated with the same HLA antigen, we studied 70 families in which at least two siblings had either type I diabetes mellitus (IDDM), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), or a combination of these diseases. HLA-A, B, and C typing was performed on all affected sibs in one generation or more. First, we estimated by sib-pair analysis the disease allele frequency (pD) and the mode of inheritance for each disease. According to the method of ascertainment entered into the analysis, the pD for ATD ranged from .120 to .180, for an additive (dominant) mode of inheritance. For RA, the pD ranged from .254 to .341, also for additive inheritance, although recessive inheritance could not be excluded. For IDDM, the pD ranged from .336 to .337 for recessive inheritance; additive inheritance was rejected. Second, we examined the distribution of shared parental haplotypes in pairs of siblings that were discordant for their autoimmune diseases. The results suggested that the same haplotype may predispose to both IDDM and ATD, or IDDM and RA, but not to both RA and ATD. Analysis of pedigrees supported this hypothesis. In 16 families typed for HLA-DR also, the haplotype predisposing to both IDDM and ATD was assigned from pedigree information to DR3 (44%), DR4 (39%), or DR5, DR6, or DR7 (5.5% each). In some families, these haplotypes segregated over several generations with ATD only (either clinical or subclinical), suggesting that in such families, ATD was a marker for a susceptibility to IDDM. In several families, an IDDM haplotype segregated with RA but not with ATD. This suggests that ATD- and RA-associated susceptibilities to IDDM may be biologically different and thus independently increase the risk of IDDM.
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PMID:Genetic interrelationship between insulin-dependent diabetes mellitus, the autoimmune thyroid diseases, and rheumatoid arthritis. 345 97

We have studied HLA-A, -B, -C, -DR, and -DQ antigen frequencies in 63 Type 1 diabetic Arab patients resident in Kuwait. Both HLA-DR3 (relative risk (RR) = 5.80) and -DR4 (RR = 2.87) showed positive associations with Type I diabetes mellitus in these patients whilst -DR2 (RR 0.16) and -DR5 (RR = 0.15) were negatively associated. The strong positive association with both HLA-DR3 and -DR4 was confirmed in Non-Gulf Arabs (RR = 12.55 and 4.29, respectively) whereas the Gulf Arabs had a significant positive association with HLA-DR3 (RR = 4.41) only. The disease was negatively associated with HLA-DR2 (RR = 0.05) in Gulf Arab patients only and with HLA-DR5 (RR = 0.10) in Non-Gulf Arabs only. HLA-DRw52 and -DRw53 were increased in Non-Gulf Arabs only (RR = 3.14 and 4.63, respectively). In both groups there was strong association with HLA-DQ3 (Gulf, RR = 28.11; Non-Gulf, RR = 6.25). Amongst HLA-A, -B, and -C loci, there was a positive association with HLA-B8 (RR = 19.06).
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PMID:HLA associations in an Arab type 1 diabetic population. 350 87

140 type 1 diabetics from Basle and vicinity were HLA-typed. 89% had HLA-haplotypes DR3, DR4, or DR3/DR4. The frequency of these antigens was significantly increased compared to normal controls. The HLA antigens DR2 and DR5 were significantly diminished in diabetics. The increase in diabetes-associated HLA antigens differed within the diabetics according to the age of diabetes manifestation. Diabetes onset before age 40 was associated with increased frequency of HLA DR4 and HLA DR3/DR4. In contrast, patients with diabetes onset after age 40 exhibited an increased prevalence of HLA DR3. The combination HLA B7/DR4 was only observed when diabetes onset was below age 20. Islet cell antibodies (ICA) were determined in 124 of the 140 type 1 diabetics. ICA were found in 40% of patients who had had diabetes for less than 2 years, but in only 21% when diabetes had lasted more than 10 years. There was no association between certain HLA haplotypes and presence of ICA. HLA antigens and the presence of ICA were also investigated in 117 first-degree relatives of the type 1 diabetics. Compared to the latter, the relatives had a significantly diminished prevalence of the HLA DR3/DR4 combination. Compared to healthy controls, these relatives had a significantly increased frequency of positive ICA (in 12% compared to 2% in nondiabetic controls). These findings demonstrate that the genetic (HLA-antigens) and immunological (ICA) background of type 1 diabetes is heterogenous. A clinical feature of the genetically determined subtypes is the age of diabetes onset.
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PMID:[HLA-antigens and islet cell antibodies in type-1 diabetics of various age groups and their first-degree relatives]. 388 21

In an ongoing prospective study 32 individuals have been evaluated for insulin secretory dynamics, islet cell antibodies and HLA antigens, during the preclinical phase of Type 1 diabetes mellitus. Twenty-four out of the 32 subjects were islet cell antibody-positive. To date, 14 subjects (10 islet cell antibody-positive, four islet cell antibody-negative) have progressed to develop overt diabetes. Several patterns of HLA-DR expression were noted (DR3/DR4, DR3/DR3, DR3/x, DR3/DR1, DR4/x, DR4/DR7, DR5/DR7, DR1/DR7 and DR1/DR2). Irrespective of differences in islet cell antibody status or HLA-DR alleles, pre-diabetic individuals exhibited a similar slow course of progressive beta-cell dysfunction.
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PMID:Pre-type 1 (insulin-dependent) diabetes: common endocrinological course despite immunological and immunogenetic heterogeneity. 638 19

Two hundred subjects with insulin-dependent (type I) diabetes mellitus (IDDM) were typed for HLA-B, HLA-DR, and properdin factor B (Bf). HLA and Bf antigen and haplotype frequencies in subjects were compared with control frequencies derived from the 8th HLA Workshop. Frequencies of extended haplotypes (defined by B-Bf-DR alleles on a chromosome) were also contrasted with control frequencies. Significant positive associations between IDDM and HLA-B8, DR3, DR4, BfS, and BfF1 were confirmed, as were significant negative associations between IDDM and HLA-B7, DR2, DR5, DR7, and BfF. One haplotype (B7-BfS-DR2) exhibited significant negative association, while five haplotypes (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4) exhibited significant positive associations with IDDM. In this sample, 64% of all probands carried at least one of the high-risk haplotypes. In conclusion, the occurrence of five "high-risk" haplotypes associated with IDDM provides evidence for previously undocumented genetic heterogeneity and suggests that possibly more than two HLA-region genes may be involved in IDDM susceptibility.
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PMID:Genetic heterogeneity of insulin-dependent (type I) diabetes mellitus: evidence from a study of extended haplotypes. 659 40

We studied fifty patients with painless thyroiditis with transient thyrotoxicosis (PTTT) and a low radioiodine thyroidal uptake. In 25 PTTT occurred post-partum (P) and in the remainder was unrelated to pregnancy (U). Seventeen patients with classical subacute thyroiditis were studied for comparison. All patients were typed for HLA-A, B, C, DR antigens. Four of the P patients had recurrences with each pregnancy; two had one previous attack of U; three had a maternal history of Graves' disease; 76% of the P patients had small to moderate goitres and 76% antimicrosomal antibody titres at greater than 1:400. HLA-B35 was found in 24% of P patients compared to 17% of controls; 71% of patients with subacute thyroiditis were, by contrast, B35. Two of P were HLA-B8 positive (versus 25% of controls); 11 patients were HLA-DR3 positive and 15 (60%) HLA-DR5 positive compared to 23% and 27% of controls yielding a relative risk (RR) = 2.50 (P less than 0.05) and 3.83 (P less than 0.005), respectively. All four P patients with recurrences carried HLA-DR5. Thirteen of 25 patients in the U subgroup were HLA-DR3, yielding a RR = 3.38 (P less than 0.01); seven were HLA-DR5, with a non-significant RR = 1.12; four of U had first degree relatives with either autoimmune thyroid disorders or Type 1 diabetes mellitus. Thus, both P and U are associated with HLA-DR3, the P subgroup had in addition an increased frequency of DR5. The observed HLA associations for the PTTT syndromes favours an autoimmune rather than viral aetiology.
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PMID:Increased frequency of HLA-DR3 and 5 in the syndromes of painless thyroiditis with transient thyrotoxicosis: evidence for an autoimmune aetiology. 660 5

Fifty-seven Thai IDDM patients were studied for HLA class I by LCT and HLA class II by LCT and PCR-RFLP. It was found that DRB1*0301, DR3, DQB1*0201, DRB3*0202, DQA1*0501 and DQ2 were significantly increased with R.R. = 10.0, 6.6, 4.2, 3.7, 3.5 and 3.2 and Pc < 0.005, 0.001, 0.01, 0.005, 0.01 and 0.005, respectively. In contrast, DQA1*0101, DRB3*0301, DR5 and DQ1 were significantly decreased with R.R. = 0.2, 0.2, 0.3 and 0.5 and Pc < 0.01, 0.05, 0.01 and 0.05, respectively. The primary factor for IDDM susceptibility is probably DRB1. The homozygous Asp57/Asp57 DQB1 genotype appears to determine resistance to IDDM while Arg52-DQA1, non-Asp57-DQB1 haplotype confers susceptibility to IDDM. The common haplotypes in Thai IDDM cases were DRB1*0301, DRB3*0202, DQA1*0501, DQB1*0201, DPB1*0401 and DRB1*0405, DQA1*0301, DQB1*0402 (or 0401 or 0302), DPB1*0401 (or 0301 or 1501). The less common haplotypes were DRB1*0406, DQA1*0301, DPB1*0302, DPB1*0501 and DRB1*1202, DRB1*0301, DQA1*0601, DQB1*0301, DPB1*0501. DR3 was increased in both gender groups with early onset (< 10 years) regardless of a family history of DM. However, DR3/DR4 genotype was increased only in female patients with a family history of DM and early onset. In conclusion, DRB1, DRB3, DQA1 and DQB1, but not DPB1 are involved in the occurrence of IDDM. The cooperation of HLA class II and X-chromosome may contribute to the development of IDDM in addition to other factors such as other genetic (chromosomes 11, 19, 14, 7), immunologic and environmental factors which require further study.
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PMID:HLA class II polymorphism in Thai insulin-dependent diabetes mellitus. 766 Mar 88


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