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

Genetic associations between type 1 diabetes and alleles at the HLA class II locus DPB1 have been previously reported. Observed associations could be due to variation in the DPB1 locus itself or to linkage disequilibrium (LD) between DPB1 alleles and other susceptibility loci. One measure of whether the association of an allele with a disease reflects a true effect of the locus or is simply due to LD is the observation of that association in multiple ethnic groups. Previous type 1 diabetes associations have been reported for DPB1*0301 and DPB1*0202 (predisposing) and for DPB1*0402 (protective). In this study, results are reported from testing these associations in three different sample sets: 1) Puerto Rican case and control subjects, 2) Mexican-American simplex families, and 3) high-risk (DR3/DR4) individuals with and without an affected relative. DPB1*0301 was associated in all three groups, even after accounting for LD with DRB1-DQB1. DPB1*0202 and DPB1*0402 were positively and negatively associated, respectively, in two of the three populations. These results suggest that the observed DPB1 associations, especially that of the DPB1*0301 allele, with type 1 diabetes are likely to be true associations. This supports the concept that multiple genes in the HLA region can affect type 1 diabetes susceptibility.
 ...
PMID:DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. 1527 1

The autoimmune disease process leading to childhood-onset type 1 diabetes appears to start in infancy, and decisions on treatment to prevent initiation of autoimmunity will need to be based on genetic susceptibility alone. We set out to quantify the absolute risk associated with human leukocyte antigen (HLA) DRB1-DQA1-DQB1 class II genotypes and to develop strategies for recruitment into primary prevention trials. HLA class II haplotype- and genotype-specific risks were derived from 753 United Kingdom families from the Bart's-Oxford population-based study of type 1 diabetes and combined with incidence data from the region to calculate the absolute risk of development of diabetes. A hierarchy of susceptibility was established for both HLA class II haplotypes and genotypes, and the sensitivity and specificity of each genotype was established relative to age at disease onset. Highest risk was conferred by the genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 (5% absolute risk of diabetes by age 15 yr), although sensitivity was only 22.6%. Combining the six highest risk genotypes conferred similar risk but increased sensitivity to 36.6% and was most sensitive for diagnosis of diabetes before age 5 yr (48.4%), whereas inclusion of 11 genotypes achieved the same sensitivity for diagnosis for ages 10-14 yr. Analysis of genotype-specific risk should form the basis for design of future primary prevention trials in the general population.
 ...
PMID:Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. 1529 46

The heterozygous combination of DQA1*03-DQB1*0302 (DQ8) and DQA1*05-DQB1*0201 (DQ2) confers the highest known HLA-DQ-linked risk for type 1 diabetes, suggesting a role for transcomplementation. The trans-heterodimer encoded by DQA1*03 and DQB1*02 is also rarely observed in cis in whites. Islet antibody-positive diabetic patients (P; n = 2,238) and control subjects (C; n = 2,223) of white descent were genotyped by a HLA-DQA1-DQB1 dot-blot method. The presence of the DQA1*03-DQB1*02 haplotype was observed in 22 patients (1%) versus 6 controls (0.3%) (odds ratio [OR] = 3.7, p = 0.005). It was more prevalent in whites of Northern African descent, but both in European (n = 3,813) and in Northern African whites (n = 648), the DQA1*03-DQB1*02 haplotype tended to be associated with diabetes (respectively, P 0.3% vs. C 0.03%, OR = 12.2, p = 0.005; and P 2.1% vs. C 0.6%, OR = 3.8, p = 0.03). DRB1 typing revealed that DQA1*03-DQB1*02 is usually associated with the DRB1*0405 risk allele in European patients and with DRB1*0405, DRB1*07 and DRB1*09 in Northern African whites. Like in DQ2/DQ8-positive patients, the presence of DQA1*03-DQB1*02 is preferentially associated with younger age at clinical onset than in other genotypes, but unlike in subjects carrying DQ2/DQ8, earlier clinical manifestation was mostly restricted to male subjects, often carrying DR3 and/or DQB1*02 on the other chromosome. These results are compatible with an effect of cis-encoded heterodimers or with previously suggested interactions of X-linked genetic factors with (DR3-)DQB1*02 haplotypes.
 ...
PMID:The rare HLA-DQA1*03-DQB1*02 haplotype confers susceptibility to type 1 diabetes in whites and is preferentially associated with early clinical disease onset in male subjects. 1530 63

DRB1*030101 is a major genetic risk factor for type 1 diabetes mellitus (T1DM) and is the only DRB1*03 allele usually seen in T1DM probands. Approximately 16% of parental DRB1*030101 alleles were not transmitted to T1DM probands in our Genetics of Kidneys and Diabetes study trio families. We performed a polymorphism screen to determine whether variations exist in DRB1*030101 alleles outside of exon 2 that may modify risk for developing T1DM. A combination of long-range and sequence-specific priming polymerase chain reaction was used to amplify a hemizygous template from both transmitted and nontransmitted parental DRB1*030101 chromosomes. Exon 2 DRB1*030101-specific and flanking DRB1-specific primers amplified the entire genomic locus as a 10.6-kb 5' fragment and a 5.3-kb 3' fragment, respectively. All exons and intron/exon borders of introns 1 and 2, all of introns 3-5, and flanking regulatory regions of 32 transmitted and 31 nontransmitted alleles (99% power to detect a 5% minimal allele frequency) were analyzed through fluorescent DNA sequencing. The only polymorphic sites detected, a previously described intron 2 complex dinucleotide repeat and an additional complex repeat approximately 1.8 kb downstream of exon 6, do not significantly differ between T1DM patients and controls in this small data set.
 ...
PMID:Polymorphism scan for differences between transmitted and nontransmitted DRB1*030101 alleles outside of exon 2 for type 1 diabetes: the frequency of polymorphisms is similar. 1530 64

There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.
 ...
PMID:Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. 1556 61

Alleles of human leukocyte antigen (HLA) class II genes are well known to affect susceptibility to type 1 diabetes (T1D), but less is known about the contribution of HLA class I alleles to T1D susceptibility. In this study, molecular genotyping was performed at the HLA-B and HLA-C loci for 283 multiplex Caucasian families, previously typed for HLA-A and the class II loci. Allele frequencies were compared between affected siblings and affected family-based controls. Linkage disequilibrium coefficients were calculated for HLA-B-HLA-C haplotypes and for class I-lass II haplotypes. After adjustment for linkage disequilibrium, the following alleles remain associated with T1D: B*1801, B*3906, B*4403, C*0303, C*0802, and C*1601. B and C allele associations were tested for certain T1D-associated DRB1-DQB1 haplotypes, with the following results: B*3801 is protective on DRB1*0401-DQB1*0302 haplotypes, both C*0701 and C*0702 are predisposing on DRB1*0404-DQB1*0302 haplotypes, and B*3906 is predisposing on DRB1*0801-DQB1*0402 haplotypes. As with previous results for HLA-A, HLA-B and HLA-C are associated with age at T1D onset (mean 11.6 +/- 0.3 years). The protective allele B*4403 was associated with older age at onset (15.1 years; p < 0.04), and the predisposing alleles C*0702 and B*3906 were associated with younger age at onset (9.5 years, p < 0.001; and 7.8 years, p < 0.002, respectively). These data support a role for HLA class I alleles in susceptibility to and age at onset of T1D.
 ...
PMID:Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. 1578 69

The present study was undertaken to clarify a role of interleukin-12p40 gene (IL-12B) polymorphism, located on chromosome 5q33-34 (IDDM 18), in Japanese subjects with Type 1 diabetes mellitus (T1DM) and autoimmune thyroid diseases (AITD). In 179 subjects with T1DM, 166 with AITD (128 with Graves' disease and 38 with Hashimoto's thyroiditis) and 115 healthy control subjects, the IL-12B 3'UTR A-C polymorphism was determined by PCR-RFLP method. In T1DM subjects, the genotype was also analyzed in relation to human leukocyte antigen (HLA)-DRB1-DQB1 haplotype status. There was a weak difference in the distribution of the genotype frequency between T1DM and control subjects, and the C allele frequency was higher in T1DM subjects (P<0.05). In 68 T1DM subjects without having high-risk HLA haplotypes to T1DM in this population, the genotype distribution and C allele frequency was significantly different from control subjects without high-risk HLA haplotypes (P<0.01), and from T1DM subjects with high-risk HLA haplotypes (n=111) (P<0.05). There was no difference in the genotype and allele frequencies between AITD and control subjects. In conclusion, the IL-12B 3'UTR A-C polymorphism did not seem to play a major role on genetic susceptibility to T1DM and AITD in Japanese, although the polymorphism conferred susceptibility in T1DM subjects without having high-risk HLA haplotypes. The IL-12B 3'UTR A-C polymorphism would be considered as a supplementary risk factor to T1DM in conjunction with HLA haplotypes.
 ...
PMID:Interleukin-12p40 gene (IL-12B) polymorphism and Type 1 diabetes mellitus in Japanese: possible role in subjects without having high-risk HLA haplotypes. 1600 98

The aim of this study was to test whether the functional variant rs2076530 of the BTNL2 gene confers susceptibility to the autoimmune diseases type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Our study populations consisted of 326 patients with T1D and 351 healthy subjects, 808 patients with RA and 1137 healthy controls, and 372 patients with SLE and 280 healthy controls. Genotyping of the BTNL2 gene rs2076530 polymorphism was performed by real-time polymerase chain reaction technology, using the TaqMan 5'-allele discrimination assay. We observed statistically significant differences in the distribution of BTNL2rs2076530 alleles between patients with T1D, RA, and SLE and healthy controls (p=0.0035, 0.000003, and 0.00002, respectively), but in two divergent ways: the G allele was associated with T1D and RA, and the A allele was associated with SLE. However, the polymorphism exhibited strong linkage disequilibrium with HLA DQB1-DRB1 haplotypes previously identified as predisposing to the diseases. When the BTNL2 polymorphism was tested conditional on HLA DQB1-DRB1haplotypes, the BTNL2 effect was no longer significant in all three study populations. The BTNL2 rs2076530 polymorphism is associated with T1D, RA, and SLE because of its strong linkage disequalibrium with predisposing HLA DQB1-DRB1 haplotypes in Caucasian populations.
 ...
PMID:Analysis of a functional BTNL2 polymorphism in type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. 1669 Apr 10

T1D (type 1 diabetes) incidence rates are extremely low in Asian populations. The prevalences of islet-specific autoantibodies are reported to be low compared with Caucasians. Although the clinical and immunologic characteristics of T1D in Asians appear to be different from those of Caucasians, if we apply correct patient definition and standardized methods, the typical T1D patients are very similar, in the immunologic as well as genetic perspectives. Although the association of individual allele seems to be different between populations, if we compare the identical DR-DQ haplotypes, the association and transmission to diabetic offspring were similar for Asians and Caucasians. The high-risk HLA genotypes/haplotypes were found to be independent determinants of diabetes in the first-degree relatives of individuals with T1D, particularly in the presence of autoantibodies. A different genetic susceptibility including a low frequency of high-risk HLA alleles could explain the lower prevalence of islet-specific autoantibodies and the low incidence of T1D, or different genetic and environmental interactions might be involved in the etiology of T1D. It is certain that DR-DQ linkage disequilibrium (LD) is an important factor explaining the difference in T1D incidence in different countries. LD between highly susceptible DRB1 alleles and protective DQB1 alleles, and vice versa, is the major contributing factor to the low incidence of T1D in Asians. We also suggested that different genetic/environmental interactions might operate in the etiology of T1D between Caucasians and Asians. It would be of great help for primary prevention to investigate to what degree genetic determinants influence the well-known regional differences in incidences, since we can identify environmental risk factors that may either initiate the autoimmune process or promote already ongoing beta cell damage in different countries. For this, population-based epidemiological studies are necessary to identify risk determinants that may be useful for primary prevention strategies.
 ...
PMID:Why is type 1 diabetes uncommon in Asia? 1713 May 29

Type 1 diabetes is a polygenic disease with a major susceptibility locus, IDDM1, located in the human leukocyte antigen (HLA) region. Although class II loci, DR and DQ genes in particular, are major components of IDDM1, accumulating lines of evidence indicated that IDDM1 consists of multiple components and that non-class II genes in addition to class II genes contribute to susceptibility to and/or age-at-onset of type 1 diabetes. To identify a second component of IDDM1, we investigated the association of a panel of polymorphisms in 2.2 Mb region of the HLA encompassing from class II to class I regions with type 1 diabetes. Polymorphisms types were: DRB1 and DQB1 in class II; two microsatellite markers, BAT2-GT and TNFa in class III; and, five microsatellite markers, STR-MICA, MIB, C1-3-1, C2-4-4, and C3-2-10 in class I region. A total of >200 Japanese patients and healthy control subjects were studied. Class II DRB1*0405 and DQB1*0401 were significantly associated with susceptibility to, but not with age-at-onset of, type 1 diabetes. C1-3-1, located near C locus, was significantly associated with not only susceptibility to, but also age-at-onset of type 1 diabetes. These data suggest that a second component of IDDM1 maps to the HLA class I region, contributing to susceptibility to as well as age-at-onset of type 1 diabetes.
 ...
PMID:A second component of HLA-linked susceptibility to type 1 diabetes maps to class I region. 1713 May 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>