Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an effort to clarify the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), a total of 230 nuclear families with pointers were analyzed using the computer program COMBIN. Each family was ascertained without deliberate selection for multiplex families, and most families were completely typed for HLA-B, HLA-DR, and properdin factor B (Bf). There were 186 families with normal parents, 44 families with one affected parent, and no families with two affected parents. The computer program COMBIN evaluates evidence for a major locus of disease susceptibility, linkage of the major locus to a known genetic marker locus, linkage disequilibrium between the marker haplotypes and disease susceptibility, pleiotropic effects, and presence of an unlinked modifier. The parameters of COMBIN are T, Q, and D, representing the displacement, gene frequency of the IDDM allele, and dominance, respectively, of the major locus--and TM, QM, and DM being the analogous parameters of the modifier. In addition, the recombination fraction, theta, between the IDDM locus and HLA as well as the coupling frequencies are estimated. Finally, COMBIN simultaneously performs segregation and linkage analysis, with the optimal model being adjusted by the fit to the haplotype sharing distribution of IDDM. The results of these analyses indicated that the best-fitting genetic model of diabetic susceptibility appears to be a single major locus with near recessivity on a scale of standardized genetic liability, with gene frequency of the IDDM susceptibility allele of approximately 14%. In addition, the recombination fraction between the major locus and HLA is zero in all models; that is, for the B-BF-DR haplotype, the IDDM locus is tightly linked, probably (according to data from previous studies) to HLA-DR. Information determined by magnitude of coupling frequencies indicated that there is significant positive linkage disequilibrium with the haplotypes B8-BfS-DR4 and B15-BfS-DR4, significant negative linkage disequilibrium with B7-BfS-DR2, and intermediate disequilibrium for B8-BfS-DR3, B18-BfF1-DR3, and B40-BfS-DR4. Significant evidence in favor of an unlinked (to HLA) modifier (either single major locus or polygenes) could not be demonstrated. In conclusion, genetic susceptibility to IDDM appears to be most consistent with a single major locus with near recessivity that is tightly linked to HLA.
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PMID:A combined segregation and linkage analysis of insulin-dependent diabetes mellitus. 357 73

HLA-A,B,C and DR typing was performed on 108 Caucasian type I diabetic patients, 68 being Gm typed. The expected association with B8, B18, Bw62, DR3 and DR4 was observed as well as an excess of DR3/4 heterozygotes. DR2 was decreased in frequency. In the total patient group, no Gm association was observed but when the patients were subgrouped according to HLA type, HLA/Gm interactive effects were seen. An increase in Gm(1,3;5) was observed in DR3 positive, DR4 negative patients. This association occurred predominantly in females (compared with DR4 and DR3/4 patients of the same Gm phenotype who were predominantly male). Further genetic heterogeneity was identified within DR3/4 patients. Within this group, Bw62 was increased (strongly suggestive of Bw62-DR4 haplotypes) within B8, Gm heterozygotes compared with B8, Gm homozygotes. This finding can be interpreted as indicating a three-way interaction between genes on two HLA haplotypes and Gm-linked genes. These results reflect the genetic heterogeneity and complexity of insulin-dependent diabetes mellitus and explain in part the previous failure of simple genetic models to adequately explain inheritance patterns observed.
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PMID:Interaction between HLA antigens and immunoglobulin (Gm) allotypes in susceptibility to type I diabetes. 372 61

We report a combined segregation and linkage analysis of a Danish sample of 216 insulin-dependent diabetes mellitus (IDDM) nuclear families: of these 216, twenty multiplex families were haplotyped regarding HLA-DR and -B markers. The analysis was conducted using the computer program COMBIN, which includes a modifier to absorb family resemblance that is additional to the effect of the major locus that is assumed linked to a marker locus, eg, within the HLA region. The initial analysis could clearly reject a dominant major locus but could not discriminate between other models with or without modifier. However, after adding supplementary information on population associations between HLA and IDDM together with the identity-by-descent (IBD) distribution to the analysis, a final model was identified. This invokes an additive major locus, linked to HLA with recombination not significantly different from 0, a disease gene frequency of 0.217, plus a dominant modifier. From this model it can be predicted that about 0.15% of the general population is at 100% risk of IDDM, about 5% is at intermediate risk (approximately 10%), while the remaining population has a risk of 0. The model predicts recurrence risks compatible with empirically estimated values. Particularly strong, positive haplotype associations were found for the DR3,B8, DR3,B18, and DR4,B15 haplotypes, but detailed analyses showed that neither these particular haplotypes nor the DR3 and DR4 haplotypes in general could entirely explain the HLA-associated susceptibility. The DR2 haplotypes showed a strong negative association. The results are discussed in the light of available data on the epidemiology of IDDM in order to provide a framework for further epidemiological studies.
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PMID:The genetic susceptibility to insulin-dependent diabetes mellitus: combined segregation and linkage analysis. 386 77

107 patients with insulin-dependent diabetes mellitus (IDDM) were typed for HLA A, B, C-, and DR antigens, and for complement C4A, C4B, and Bf alleles, and the results were compared with those of a combined reference group of 332 appropriately matched healthy subjects. Supratypes (allelic combinations) were identified from the phenotype of each group, and it was shown that the frequency of several supratypes is increased in patients with IDDM, in particular supratypes (A1 Cw7) B8 C4AQ0 C4B1 BfS DR3 (P = 0.0001), (A30 Cw-) B18 C4A3 C4BQ0 BfF1 DR3 (P = 0.0003), (A2 Cw3) B62 C4AR C4B2.9 BfS DR4 (P = 0.0002), and three other supratypes including DR4. It was also shown that increases in the frequency of individual alleles are secondary to increases in supratype frequency. Moreover, supratypes appeared to interact; the presence of two relevant supratypes being particularly important. The absolute risk of IDDM was approximately 0.5 in subjects who were homozygous for B18 C4A3 C4BQ0 BfF1 DR3. We concluded that genetic susceptibility is best recognized by MHC supratypes rather than isolated alleles, and that supratype combinations make the identification of even greater disease risk possible.
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PMID:Susceptibility to IDDM is marked by MHC supratypes rather than individual alleles. 386 95

A remission defined by the possibility of temporarily discontinuing insulin therapy while blood glucose remains normal is not infrequently observed after intensive insulin therapy in newly diagnosed acute type I diabetes in the South of France. In order to analyze possible factors of such a remission, 47 newly diagnosed ketotic diabetics under 35 years of age and of Caucasian origin were enrolled in a prospective study. They were given continuous s.c. insulin infusion for two weeks and oral agents were introduced on day 8. In 16 patients insulin could not be withdrawn. In 31 insulin was stopped for more than 3 months (mean 12.3, range 3-35) while blood glucose remained below 6 mmol/l fasting (mean 5.3) and 7.8 post-prandial (mean 5.1) and glycosylated Hb below 8.5% (mean 6). At presentation, diabetics who later went into remission and those who did not, showed no difference in age (22.3 vs 23.1 years), sex ratio, apparent duration of symptoms (1.4 vs 1.6 months), glycosylated hemoglobin (12.0 vs 13.1%) and basal or post-prandial C-peptide values or presence of islet cell antibodies. No differences were observed in the frequency of DR3 and DR4 antigens in the two groups but diabetics who developed a remission bore the A 19.2 antigen (9/31 vs 1/16) and the B18 one (11/31 vs 1/16) more frequently, A 19.2 and B18 being associated in 7 cases of this group. This increased frequency in the remission group of HLA antigens, more often observed in diabetics of Mediterranean origin, suggests that differences in the genetic background may be associated with a difference in the evolution of the disease.
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PMID:Sustained initial remission induced by intensive insulin treatment in type I diabetes. Possible role of the genetic background. 391 56

The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLA-A, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 May
PMID:Complement and HLA. Further definition of high-risk haplotypes in insulin-dependent diabetes. 398 76

For a preliminary estimation of the prevalence and significance of HLA antigens, tests were carried out on the A and B loci in an unselected group of 107 patients with type 1 diabetes in Bucharest. Monospecific antisera furnished by NIH, Bethesda were used. For HLA-A the following data were obtained: A2 (20.3% of the total specificities); A1 (18.4%); A3 (14.0%); A28 (10.1%). Provisional estimations in the healthy population also indicated HLA-A2 as being more frequent than followed by A30/31, A1, A9, A3. For HLA-B: B7 (38.2%); B5, B12 and B14 (14.0% each); B8 (11.1%). In the healthy subjects, the order was B12, B35, B5, B8 the same as B18, then B7 (which did not exceed 11%). The most frequently encountered haplotypes in the diabetic patients were: A2/B7 (8.4% of the total haplotypes); A3/B7 (6.9%); A1/B7 (6.6%); A10/B7 (3.8%); A9/B7 and A11/B7 (3.6% each). An unexpectedly high frequency of the HLA-B7 antigen was found in group of diabetic patients investigated, contrasting with its assumed "protector" role in the Caucasian population. The frequency of antigen HLA-A3 and haplotype HLA-A3/B7 infringes their listing in the "resistance axis" to diabetes.
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PMID:Testing histocompatibility antigens (loci A and B) in a group of type 1 (insulin-dependent) diabetic patients in Bucharest. 404 1

Changes in the incidence of the HLA system antigens (A1, A2, A3, A9, A10, A11, A19, A28, A29, B5, B7, B8, B13, B14, B15, B16, B17, B18, B21, B22, B27, B35, B37, B40, B41) was studied in 1134 healthy persons and in 147 patients with diabetes mellitus. In comparison with healthy persons, patients with juvenile diabetes mellitus (62) displayed a significant increase in the incidence of antigens B8, B15, B35, and A10, and patients with adult diabetes mellitus with normal weight (35)--of antigen B8. When adult diabetes mellitus was accompanied by obesity (50) a significant rise in the occurrence of antigen A10 was revealed.
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PMID:[Change in the incidence of HL-A antigens in diabetes mellitus]. 615 26

Three groups of patients with insulin-dependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n = 164), and a subset (n = 93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR+ was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system.
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PMID:HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus. 616 81

We describe three human proliferating T cell colonies, derived from mixed leukocyte culture with a non-diabetic individual (DR3 + 4) as the source of responding cells and an insulin-dependent diabetic patient (also DR3 + 4) as the source of stimulating cells. One colony detects HLA-Dw10 or a closely related antigen, and two detect an antigen that we call BO1 (Boston 1). BO1 is found so far on cells of all persons with DR5, about half of those with DRw6, and a particular subset of those with DR3. Among DR3-positive subjects, BO1 is positively correlated with HLA-B18 and BfF1, and negatively correlated with HLA-B8. These findings suggest that BO1 occurs in linkage disequilibrium with DR5, DRw6, and the haplotype B18, BfF1, DR3, the latter being common in southern Europe and reported previously to be a marker for insulin-dependent diabetes. In limited testing (21 subjects), BO1 was completely included in the supertypic specificity MT2, BO1 is a Class II HLA antigen, as demonstrated by blocking with monoclonal antibodies, but is distinct from all known antigens of the DR, MB(DC), MT, and SB series. It could be located on the same polypeptide chain as one or more of these antigen groups, however, particularly DR and/or MT.
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PMID:HLA antigens of insulin-dependent diabetics. I. PLT colonies detecting Dw10 and a new class II determinant distinct from HLA-D, DR, MB(DC), MT, and SB. 620 68


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