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 control of insulin dependent diabetes mellitus (IDDM) is mainly dependent on HLA genes in the major histocompatibility complex (MHC). The participation of TAP1 and TAP2 genes, located in the MHC region and coding for antigenic peptide transporters, was investigated in 116 IDDM patients and 98 normal controls using oligotyping after DNA amplification. The TAP2-B allele had a dominant protective effect, additive to that of the DR2 haplotype but antagonist to the susceptibility associated with the DR3 and/or DR4 haplotypes. The TAP2-A allele, in the homozygous state, had a predisposing effect. TAP1 allelic distribution did not differ among IDDM patients and controls. These data argue in favour of the role of peptide transporter gene in diabetogenesis.
 ...
PMID:TAP1 and TAP2 transporter genes and predisposition to insulin dependent diabetes mellitus. 130 Feb 36

IDDM is known to be associated with genes of HLA complex, particularly alleles of HLA-DQ. The 40-kb TAP gene complex is located approximately 150 kb centrometric to the DQB1 locus. The TAP1-TAP2 protein heterodimer is required for normal expression levels of class I, molecules on the surface of cells. While present evidence implicates HLA-DQ as the major susceptibility locus in IDDM, as class I expression apparently plays a role in the progression of disease, the possibility exists that the association attributed to HLA-DQ is in fact due to an association with the TAP genes. Several studies have concluded that the alleles of TAP1 are not significantly associated with IDDM; this report concentrates on the more telomeric TAP2 locus. During this investigation, six previously described TAP2 alleles were identified in 208 normal Caucasians and 241 Caucasian diabetics. Sequence analysis of cDNA clones identified a seventh allele of TAP2, TAP2*F, which contains an arginine-to-cystine interchange at amino acid position 651. Overall, our results indicate only a modest association of IDDM with TAP2; however, the newly described TAP2*F allele was found to be significantly increased in a modest subset of our large diabetic population. These data, generated from the same population of controls and diabetics we previously studied at all other relevant MHC loci, provide additional evidence that the HLA susceptibility to IDDM maps to HLA-DQ.
 ...
PMID:TAP2 association with insulin-dependent diabetes mellitus is secondary to HLA-DQB1. 755 30

The TAP2 gene, located in the HLA class II region, encodes a subunit of a transporter involved in the endogenous antigen-processing pathway, and has been suggested to contribute to the genetic risk for insulin-dependent diabetes (IDDM). In order to determine whether the TAP2 locus modulates the risk conferred by HLA DQ loci, HLA DQA1-DQB1-TAP2 haplotypes were analysed in 48 IDDM probands, their first degree relatives, and in 62 normal control subjects. A decreased frequency of the TAP2B allele was confirmed in this IDDM cohort (12 vs 28% in control subjects, pc < 0.05). Analysis of 73 informative meiotic events in IDDM and control families demonstrated a recombination fraction between HLA DQB1 and TAP2 loci of 0.041 (Log of the odds score = 16.5; p < 10(-8)) indicating strong linkage between these loci. Family haplotype analysis demonstrated linkage disequilibrium between TAP2 and HLA DQA1-DQB1, and showed that the reduced frequency of TAP2B was associated with its absence on the IDDM susceptible DQA1*0301-DQB1*0302 haplotype, its low frequency on DQA1*0501-DQB1*0201, and the association of TAP2B with DQA1*0101-DQB1*0501 haplotypes which were less frequent in IDDM patients. Comparison of transmitted with non-transmitted haplotypes in IDDM families showed a slight but not significant decrease in TAP2B allele frequency on transmitted (3 of 37) vs non-transmitted (2 of 9) HLA DQA1*0501-DQB1*0201 haplotypes. No other differences were observed. Twenty-four unrelated DQA1*0501-DQB1*0201 haplotypes from non-diabetic families had a TAP2B allele frequency (4%) similar to that in IDDM haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:HLA DQA1-DQB1-TAP2 haplotypes in IDDM families: no evidence for an additional contribution to disease risk by the TAP2 locus. 758 84

Although one of the major genes which cause type 1 (insulin-dependent) diabetes mellitus is located in the class II HLA region in humans, its precise location is still unknown. In order to investigate whether TAP (Transporter associated with Antigen Processing) and LMP (Low Molecular Weight Polypeptide) genes, which are located in the class II HLA region, are HLA-linked diabetogenic genes, the association of TAP1, TAP2 and LMP2 genes with type 1 diabetes was analyzed in the Japanese population. No difference in allele frequencies of these genes was detected between diabetic patients and control subjects. On the other hand, DQA1 and DQB1 genes showed significant association with type 1 diabetes. These data suggest that the diabetogenic gene in the class II HLA region may be located near the DQA1 and DQB1 loci, rather than the TAP and LMP loci.
 ...
PMID:Absence of association of TAP and LMP genes with type 1 (insulin-dependent) diabetes mellitus. 791 50

We examined the prevalence of HLA-DRB1, DQB1, DQA1 and TAP2 genes in children with insulin-dependent diabetes mellitus (type 1 diabetes). These HLA and TAP2 alleles were identified by dot-blot analysis of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotide probes. The results show that those DQB1 alleles, which carry non-aspartic acid at position 57, in conjunction with DQA1 alleles carrying arginine at position 52, are strongly associated with susceptibility to type 1 diabetes. The prevalence of the TAP2* 0201 allele in diabetic patients was significantly lower than that in normal controls. Analysis of the data suggests that DQ alleles have the primary association with type 1 diabetes and that the association of TAP2 alleles with the disease is secondary.
 ...
PMID:HLA-DQ and TAP2 genes in patients with insulin-dependent diabetes mellitus. 800 38

The transporter associated with antigen processing (TAP) encoded in the major histocompatibility complex (MHC) class II region is a molecule required for endogenous antigen processing. We have typed TAP polymorphism in 95 Japanese patients with insulin-dependent diabetes mellitus (DDM) and 75 normal controls. Amino acid substitutions at positions 333 and 637 of TAP1 and at positions 379, 665, and 687 of TAP2 were typed by the polymerase chain reaction (PCR)-sequence-specific oligonucleotide method. In addition, DNA typing of human leukocyte antigen (HLA)-DQA1 and -DQB1 loci was performed by the PCR-restriction fragment length polymorphism method. There was no significant difference between IDDM patients and normal controls in the frequencies of TAP1 and TAP2 alleles. On the contrary, the HLA-DQ locus showed a strong association with IDDM in the same series of subjects. The frequencies of HLA-DQA1*0301 and -DQB1*0401 were increased significantly and those of HLA-DQA1*0103, -DQB1*0501, -DQB1*0601 and -DQB1*0602 were decreased significantly in Japanese IDDM patients compared with normal controls. Positive linkage disequilibrium was observed between HLA-DQB1*0303 and TAP2C and between HLA-DQB1*0401 and TAP2B. Negative linkage disequilibrium was observed between HLA-DQA1*0103 and TAP2A. Even when subjects with HLA-DQA1*0103, -DQA1*0301, -DQB1*0302, -DQB1*0303, and -DQB1*0401 were considered separately, no significant differences was found in the distribution of TAP1 and TAP2 alleles between IDDM patients and normal controls. We conclude that it is not TAP but HLA-DQ that exhibits a primary association with Japanese IDDM.
 ...
PMID:Lack of association of the transporter associated with antigen processing with Japanese insulin-dependent diabetes mellitus. 805 40

Stable cell surface presentation of MHC class I molecules requires active transport of antigenic peptides across the endoplasmic reticulum by products of two genes, TAP1 and TAP2, which are maped in the MHC class II region. There are many human diseases whose onset are associated with particular MHC alleles. However it has not always been possible to assign susceptibility to individual genes because genes within the complex are in linkage disequilibrium. In this study, we tested DNA from sixty-three healthy controls and 64 Insulin Dependent Diabetes Mellitus: IDDM patients by Polymerase Chain Reaction-Sequence Specific Oligonucleotide: PCR-SSO, Polymerase Chain Reaction-Single Strand Conformation Polymorphism: PCR-SSCP analysis and DNA sequencing. These studies demonstrated the difference in frequencies of TAP2 gene products between healthy control and IDDM patient, and between Japanese and Caucasian population. Statistic analysis of HLA antigens and variants amino acids of TAP showed the linkage disequilibrium between TAP2-665, -687 sequence and HLA-DR alleles. The data suggests that the association of TAP2 allele with IDDM disease may be a simple reflection of the linkage disequilibrium between TAP allele and DR4 gene.
 ...
PMID:[Polymorphism of the TAP genes Japanese healthy control and type I diabetes mellitus]. 815 58

The polymorphic TAP1 and TAP2 genes encode a transporter protein required for delivery of cytosolic peptides to class I molecules in the endoplasmic reticulum. Associations have been observed between TAP2 alleles and predisposition to autoimmune diseases such as IDDM but their interpretation has been complicated by the existence of LD between TAP2 and HLA class II loci, and conclusions are still contradictory. In order to precisely define LD on class II haplotypes, we performed an extensive familial analysis. A total of 466 individuals from 55 normal families and 49 IDDM multiplex families was studied, providing information on 420 independent haplotypes. The IDDM-predisposing DRB1*03 and DRB1*04 alleles were in strong negative LD with TAP2-B (delta = -0.035 and -0.034, respectively), and positive LD with TAP2-A (delta = + 0.055 and + 0.012). Positive LD was also found between TAP2-B and DRB1*01 and TAP2-C and DRB1*11 alleles. We then addressed the question of whether TAP2 is an independent additional IDDM-protective or predisposing genetic factor. No TAP2 effect was evidenced when considering DRB1*03 and/or 04 patients. A decreased TAP2-B phenotype frequency was observed in DRB1*03- and DRB1*04-negative IDDM patients compared with DRB1*03- and DRB1*04-negative normal controls (38.6% vs 63%, pc < 0.05), but was probably related to a combination of different weak LD between DRB1 and TAP2 alleles. It thus appears that there is no primary association between TAP2 alleles and IDDM. However, TAP polymorphism may allow us to define particular extended HLA haplotypes involved in susceptibility to autoimmune diseases.
 ...
PMID:Family study of linkage disequilibrium between TAP2 transporter and HLA class II genes. Absence of TAP2 contribution to association with insulin-dependent diabetes mellitus. 884 32

The aim of this study was to compare the genetic susceptibility linked to the HLA Class II region genes of the Major Histocompatibility Complex in isolated insulin-dependent diabetes mellitus (1a-IDDM) and insulin-dependent diabetes mellitus associated with another autoimmune endocrinopathy (1b-IDDM). HLA genes DRB1, DQA1 and DQB1 were studied at the genomic level, as well as genes TAP1 and TAP2. One hundred and seventy-nine 1a-IDDM diabetic patients were compared with 83 1b-IDDM patients. While it appeared that common genetic traits characterize diabetes regardless of the subtype (1a or 1b), certain features differentiate the two forms of IDDM. Extending the analysis of risk haplotypes DRB1*03 and DRB1*04 to TAP genes elicited a difference between 1a-IDDM and 1b-IDDM patients. Haplo-type DRB1*03 was thus characterized in 1a-IDDM patients by a lower frequency of alleles TAP1-B (13.5%) and TAP2-B (16.2%), not found in 1b-IDDM patients (33.3% for each allele). Likewise, haplotype DRB1*04 is characterized in 1b-IDDM patients by a lower frequency of alleles TAP1-C (4.0%) and TAP2-B (8.0%) than in 1a-IDDM patients (22.2% and 25.9%, respectively). In total, this study showed that extending the characterization of HLA Class II haplotypes to TAP genes discriminates between the forms of diabetes restricted to a specific pancreatic affection and those reflecting a wider autoimmune disorder affecting several organs.
 ...
PMID:Genetic heterogeneity between type 1a and type 1b insulin-dependent diabetes mellitus: HLA class II and TAP gene analysis. 898 36

Type 1 diabetes mellitus (IDDM) is an autoimmune disorder in which the alleles HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 confer strong susceptibility. The genes for transporters associated with antigen processing (TAP1 and TAP2) are located near HLA DQ and display only a limited degree of polymorphism. Since polymorphisms of TAP might influence susceptibility to IDDM possibly by selection of different antigen peptides, we investigated sequence variants of TAP1 and TAP2 genes in 120 German patients with IDDM and 218 random healthy German controls by polymerase chain reaction (PCR) followed by sequence-specific oligonucleotide analysis (SSO), single-strand conformation polymorphism (SSCP) analysis and amplification refractory mutation system (ARMS). TAP1*02011 (16% vs. 4% in controls, P = 0.001, RR = 5.0) and TAP2*0101 (96% vs. 69% in controls, P < 0.0001, RR = 10.6) showed a positive association with IDDM. However, these associations disappeared when patients and controls were matched for predisposing HLA DQA1 or DQB1 alleles as well as for DRB1*0401. In conclusion, our findings indicate that the observed association of TAP variants with IDDM in German patients is due to linkage disequilibrium with HLA DQ alleles/DRB1*04 subtypes.
 ...
PMID:Polymorphisms of TAP1 and TAP2 genes in German patients with type 1 diabetes mellitus. 922 29


1 2 Next >>