Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is caused by the destruction of the beta cells of the pancreas. This process is associated with the presence of islet cell antibodies (ICA). The risk for developing IDDM is associated closely with the presence of the HLA type DR3 and/or DR4. The risk is greatest for those with both DR3 and DR4. Recent evidence indicates that the DR antigens are only expressed in the beta cells of individuals who are developing IDDM. Activation of the DR antigen in beta cells apparently plays a role in the pathogenesis of IDDM. A process that turns off the expression of the DR antigen may stop the destruction of the beta cells. Preliminary evidence indicates that total suppression of beta cell function with an artificial pancreas (Biostator) significantly prolongs beta cell function well beyond that reported for immunosuppressive drugs. The Biostator may work by total suppression of beta cell function, which turns off the expression of the DR antigen with a resultant cessation of beta cell destruction.
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PMID:Southern Society for Pediatric Research. Presidential address: What is causing diabetes in children? 330 6

Seventy IDDM patients (insulin-dependent diabetics), 48 females and 22 males, most of them adults at the onset of diabetes, and suffering from at least one other associated autoimmune manifestation (AAM) were studied for HLA A,B,C, DR markers and Bf, C4 complement components. Comparisons were made with 108 normal controls and a series of 287 IDDM patients with juvenile onset (under 25 years) and no patent other autoimmune disease. The increase in frequency of HLA-B8 among IDDM patients with AAM was confirmed (36% versus 20% in controls) (p less than 0.04). The frequency of DR4 among diabetics with AAM (33%) was not significantly different from the normal frequency (27%), and the allelic combination DR3/4 was found in only 13% of IDDM with AAM. Corresponding frequencies in patients with IDDM alone were 66% for DR4 and 34% for DR3/4 (p less than 10(-6) and 10(-3) respectively). These results confirm the heterogeneity of IDDM and support, by genetic arguments, the concept of overlapping entities. The hypothesis of a common background of autoimmunity associated with B8 DR3 can be postulated, while the organ specific target process should be associated with various DR alleles.
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PMID:MHC classes I, II, III antigens study in 70 insulin-dependent diabetics with associated auto-immune diseases. 340 88

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

In order to discover the HLA DR antigens linked to Japanese insulin-dependent diabetes (IDDM), and to relate them to the clinical features, HLA DR antigens were examined in 75 IDDM patients including 56 adult-onset cases. Among the tested HLA DR antigens, 4, w9 and w13 were significantly more frequent in IDDM (55%, 47% and 27% respectively). The relative risk was 1.71 for DR4, 2.81 for DRw9 and 4.74 for DRw13. DR2 was significantly less frequent and the relative risk was 0.14. The distribution of DR antigens did not differ between juvenile-onset and adult-onset IDDM, males and females, or cases with and without thyroid autoantibodies. Homozygotes for DRw9 were, but those for DRw13 and DR4 were not more frequent than expected by a random combination. Heterozygotes for DR4 and w9 were less frequent while other heterozygotes for high-risk antigens were as frequent as expected. 97% of IDDM had either DR4, w9 or w13. In conclusion, HLA DR4, w9 and w13 were significantly increased in patients with both juvenile- and adult-onset IDDM. There was no surplus increase in the frequency of IDDM patients with two high-risk HLA DR antigens, more than expected from random combination of each of these DR antigens. Clinical features did not differ among IDDM patients with each of these three antigens.
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PMID:HLA DR antigens in adult-onset and juvenile-onset Japanese insulin-dependent diabetic patients. 341 8

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

One hundred and thirty-six Finnish patients with insulin-dependent (type I) diabetes mellitus were investigated for the HLA-A, B, D and DR antigens as well as the Bf and C4 allotypes. The statistically significant increase in the frequencies of HLA-A9, B8, B15, Dw3, Dw4, DR3, DR4, C4A0 and C4B3 was observed when compared with the healthy controls. About 79% of the patients had HLA-DR4, and 53% had HLA-DR3 antigens. A rare C4 allele C4B3 was found in 21% of the patients, whereas only in 2% among the controls (relative risk 16.35). The etiological fraction (EF) values indicated that HLA D/DR alleles were the best markers for IDDM, the observed EF for HLA-DR4 in diabetes was as high as 0.70. Examination of HLA, Bf and C4 phenotypes suggested that at least two supratypes "B15 BfS C4A3B3 D(R)4" and "B8 BfS C4A0B1 D(R)3" were markers for the susceptibility to type I diabetes, one third of our patients had either of these supratypes. The protective role of DR2 and Dw2 antigens was also confirmed: no HLA-Dw2 positive patients and only one with HLA-DR2 was found.
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PMID:HLA antigens and complotypes in insulin-dependent diabetes mellitus. 346 Feb 20

DR4 and DR3 are in strongest linkage disequilibrium with IDDM susceptibility genes, and DR1 demonstrates a lesser degree of positive disequilibrium. DR3/DR4 heterozygotes have the highest risk. The DR1 increase occurs almost exclusively in DR4/DR1 heterozygotes, suggesting that DR1 may be in disequilibrium with the same susceptibility gene as DR3. Homozygotes for DR4 and especially DR3 have a higher risk than heterozygotes of either with DRX. GLO-2 is increased in diabetic haplotypes carrying DR4, DR3 or DR1.
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PMID:HLA-DR effects in a large German IDDM dataset. 347 65

Insulin-dependent diabetes mellitus (IDDM) susceptibility determinants are known to be associated with both HLA-DR3 and -DR4. We monitored the inheritance of HLA-DR alleles in 37 families in which IDDM affected one parent and at least one offspring in order to try to learn more about the modes of inheritance of IDDM determinants. Ninety-seven insulin-dependent diabetics whose parents did not have diabetes and 158 nondiabetics were used as control groups for estimates of DR allele frequencies in the overall diabetic and general populations. The proportion of diabetic parents who transmitted DR4 to diabetic offspring (78%) was significantly higher (P less than 0.001) than the gene frequency of DR4 in the overall diabetic population (43%). The proportion of nondiabetic parents who transmitted DR4 to diabetic offspring (22%) was not significantly different from the gene frequency of DR4 in the nondiabetic population (16%), but it was significantly lower (P less than 0.05) than the gene frequency in the overall IDDM population. These proportions suggest that inheritance of the DR4-associated IDDM susceptibility determinant is not recessive, because in recessive inheritance expression of a trait depends on each parent contributing a susceptibility determinant. The proportions of diabetic and nondiabetic parents who transmitted the DR allele associated with the susceptibility determinant would then equal one another. The transmission of predominantly DR4 from affected parents to affected offspring suggests that susceptibility to IDDM is inherited primarily via a single dose of a potent determinant associated with DR4, as in dominant inheritance. When DR3 was transmitted at all it was usually by the nondiabetic parent. Only 8% of diabetic parents transmitted DR3 but 35% of nondiabetic parents transmitted DR3. The proportion of nondiabetic parents who transmitted DR3 was similar to the gene frequency of DR3 in the overall diabetic population (29%), but it was significantly higher than the gene frequency of DR3 in the nondiabetic population (15%; P less than 0.005). The percentage of diabetic offspring with the genotype DR3DR4 (35%) was identical to the percentage of individuals in the overall IDDM population with this genotype (35%). Numerous population data indicate that the DR3DR4 genotype carries a higher relative risk for IDDM than any other genotype, which suggests synergism between the DR3- and DR4-associated determinants. The family data reported here support this synergism but suggest that the DR4-associated determinant can give substantial susceptibility independent of the DR3-associated determinant and that the DR3-associated determinant is often expressed as enhancing susceptibility in the presence of the dominant DR4- associated determinant.
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PMID:HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance. 348 37

Type 1 diabetes is said to be extremely rare in children in India, where diabetes treated with insulin may be due to chronic pancreatic disease or malnutrition. To see whether typical type 1 diabetes occurred in Asian children in the United Kingdom, all known Asian children with diabetes in industrial West Yorkshire were ascertained. A total of 17 such children were studied; of these, seven were from three multiplex families and two fathers from these families had diabetes. All children were ketosis prone and developed diabetes while resident in the UK. There were significant increases in HLA-B8 and HLA-DR3 and increases in HLA-DR4 and HLA-DR3/DR4, while HLA-B15 was absent. Islet cell antibodies, either IgG or complement fixing, were present in four of 18 subjects tested, all of whom had disease of short duration. The prevalence of type 1 diabetes in Asian children aged 15 years or less in West Yorkshire was 36/100,000, assuming complete ascertainment. It is concluded that typical type 1 diabetes may occur in Asian children and this condition may be more common in families who have migrated to the UK.
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PMID:Insulin dependent diabetes in Asians. 349 31

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


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