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)

A major component of inherited susceptibility to IDDM is associated with one or more loci in the MHC. Identification of the primary susceptibility genes has been complicated by the low frequency of recombination, i.e. linkage disequilibrium, within the MHC. It is difficult to distinguish whether a detected genetic association with the disease is primary, or secondary due to linkage disequilibrium with an allele at another locus which is directly predisposing. During the evolution of different races, however, recombination within the MHC has occurred and population-specific MHC haplotypes exist. Primary susceptibility allels should be associated with disease in all racial groups, regardless of genetic background. It is unlikely that disease associations secondary to linkage disequilibrium will be consistent in these groups. This chapter reviews the known associations of candidate class II susceptibility alleles with IDDM in the five largest racial groups; white Caucasians, Asian Indians, Negroids, Japanese and Chinese. These trans-racial studies suggest that the DQ molecule has a primary role in predisposition to IDDM. There are consistent findings of a positive association with the DQA1*0301 allele and negative associations with the DQB1*0602 and DQB1*0603 alleles. These two alleles differ by a single codon and so the encoded DQ beta chains are likely to have similar functions. DR4-associated susceptibility is associated with the DQA1*0301 allele in all races tested so far but this allele cannot be the only susceptibility factor on this haplotype. The identity of the DR3-associated susceptibility factor remains unclear but the DQB1*0201 allele is a candidate. If DQB1*0201 is involved, the existence of a protective factor on the neutral DR7-DQB1*0201 haplotypes is indicated. Analysis of DR9 associated susceptibility implicates a non-DR/DQ predisposing factor.
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PMID:Genetics of diabetes. Trans-racial gene mapping studies. 189 69

Studies of various insulin-dependent diabetes mellitus (IDDM) populations have shown that certain HLA antigens confer a high risk of developing disease. There is very little information concerning the distribution of HLA antigens in type 1 diabetes in the Turkish population. In this study, the HLA types of 75 patients and 50 controls were investigated. HLA-DR3 and HLA-DR4 were found more frequently in the IDDM cases (p = 0.0018 and 0.0119, respectively). DR3/DR4, although more frequent, did not achieve statistical significance. The decreased frequencies of DR1 and DR2 in the IDDM population were not significant whereas the DR7 was found to be significantly decreased (p = 0.025). The younger age of onset was strongly associated with DR4 (p = 0.0029). DR3 was more common among the male and DR4 in the female patients. However, the differences were not significant.
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PMID:The type 1 diabetes and HLA-DR in Turkey. 191 1

We investigated polymorphism of HLA-DP genes in three DR3 related diseases, confirming an association of coeliac disease with a Bgl II DP alpha polymorphism (a restriction fragment sized 3.5 kb present in 75% of patients compared to 34% of control subjects, p less than 0.001), and finding a weaker association with dermatitis herpetiformis (57% v 34%, p = 0.01) and no association with insulin dependent diabetes mellitus. The association with coeliac disease was further investigated. Msp I DP beta polymorphism was studied in 52 healthy subjects and 59 patients: a 4.9 kb fragment was present in 51% of patients with coeliac disease compared to 11.5% of control subjects (p less than 0.001). Furthermore, nearly all subjects with the DP alpha 3.5 kb fragment also had the DP beta 4.9 kb fragment. However, disease frequency was still increased in the DP alpha 3.5 positive/DP beta 4.9 negative group. In seven families, each with at least two affected members, while the DP alpha 3.5 fragment was frequently present in patients it did not preferentially segregate with any particular HLA haplotype--for example, those associated with DR3 or DR7--and therefore is not part of an extended haplotype associated with coeliac disease. We therefore conclude that a gene(s) in the HLA-DP region predisposes to coeliac disease independently of the HLA-DR/DQ regions.
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PMID:HLA-DP and coeliac disease: family and population studies. 197 34

Insulin-dependent diabetes mellitus is associated with an increased frequency of certain histocompatibility antigens located on chromosome six, the most common types being B-8, B-15, DR-3, DR-4, and DR-7. We therefore theorized that screening for these subtypes may allow the identification of those women with gestational diabetes who will remain euglycemic on dietary modification (class A1) compared with those who will require insulin to achieve euglycemia (class GB). From 1982 to 1987, 228 black women with gestational diabetes were screened for the above histocompatibility antigens. As theorized, certain histocompatibility antigen subtypes were more common in women with class GB gestational diabetes mellitus; DR-2 (41.8% versus 23.7% p = 0.015), B-15 (p = 0.07), and DR-3 (p = 0.08). However, because of the low sensitivity (42%), specificity (75%), and positive predictive value (36%), this test is impractical in the clinical management of women with gestational diabetes mellitus.
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PMID:Histocompatibility antigen subtypes in black women with class A1 or class GB diabetes mellitus. 200 34

1. The mode of inheritance of the DR3- and DR4-associated susceptibility genotype is essentially recessive, based on both the segregation data and the existence of Hardy-Weinberg equilibrium in Ashkenazi Jewish and possibly in patients of other populations. 2. Maternal effects may alter the expressivity of IDDM in some susceptible offspring, depending on the maternal DR genotype. Thus, the number of susceptible DR4 types inherited from the mothers may be decreased in certain population samples. Conceivably, these maternal effects also account for the smaller proportion of diabetic children born to diabetic women than to diabetic men. Conversely, maternal DRw6 may raise this risk. 3. The locus of the susceptibility gene is most likely in the DQ region. While specific DQA1 and DQB1 alleles are very closely associated with IDDM in some populations, neither is completely associated with it in DR4 haplotypes and neither accounts for the differences in IDDM susceptibility associated with DR3 haplotypes. 4. Linkage disequilibrium between DR and DP alleles in affected haplotypes indicates the existence of subsets of DR3 and DR7, which account for all or most of the risk to those haplotypes. The possibility of direct DP effects is less likely because the respective DP alleles are different and because DR4 does not maintain disequilibrium with DP alleles in either affected or unaffected haplotypes. 5. The DQA2-BglII-7.2Kb polymorphism in complete association with affected B8,DR3 haplotypes suggests the possible involvement of DQA2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA and IDDM: facts and speculations on the disease gene and its mode of inheritance. 204 89

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 investigated DNA polymorphism of the class II alpha chain genes in HLA typed patients with insulin dependent diabetes mellitus (IDDM; n = 79), celiac disease (CD; n = 46), dermatitis herpetiformis (DH; n = 53), and controls (n = 86). Preferential allelic associations of HLA genes and gene products have thus been constructed for susceptibility to these diseases. DR alpha and DQ alpha gene polymorphisms indicated heterogeneity of HLA DR3, DRw6, and DR7, and HLA DR2 and DRw6, respectively. In DR7 positive CD patients a 3.8-kilobase (kb) DR alpha fragment, which correlated with DQw3, was found in only 11% of patients compared with 45% of corresponding controls (P less than 0.05). An increased frequency of a DX alpha genotype UU in all three diseases was found (IDDM 59%, DH 45%, CD 48%, compared to 21% in controls, P less than 0.001), which is not explained solely by the increased frequencies of DR3-DX alpha U. We therefore conclude part of the genetic susceptibility for these three conditions is encoded by genes within the DQ-DX subregion.
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PMID:HLA class II alpha chain gene polymorphisms in patients with insulin-dependent diabetes mellitus, dermatitis herpetiformis, and celiac disease. 380 83

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

In order to try to detect heterogeneity within insulin dependent diabetes mellitus (IDDM) and to distinguish a mode of inheritance of IDDM, population genetic analyses were performed using HLA allele frequencies. HLA-A and -B typing performed on 231 IDDM individuals and 268 controls from the southeastern U.S. showed significant increases with IDDM in A2, B8, B15 and B18, and significant decreases in Aw23, B7, B14 and B17. The combination of HLA-B8/B15 showed a greatly increased risk (RR = 25.5). Between the 120 IDDM individuals and 123 controls HLA-DR typed, HLA-DR3 and -DR4 were significantly increased among the IDDM group and DR2 and DR7 were decreased. The risk for DR3/4 was 29.2. It appeared that the B15 association was secondary to the DR4, but the B8/DR3 association showed no difference. Using the method of Curie-Cohen, no significant increases in risk were found for the B8/B15 or DR3/DR4 heterozygotes when compared to the respective homozygotes. Using the method of Thomson and Bodmer, the dominant mode of inheritance was excluded for DR4 only. There was a significant increase in B15 and DR4 in those with onset before age 20. No significant differences were found among the DR phenotypes with respect to season.
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PMID:Population genetic analyses of insulin dependent diabetes mellitus using HLA allele frequencies. 641 98


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