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)

HLA class II associations with IDDM in populations of non-Caucasoid origin can provide important insights into the nature of the HLA and disease association. Firstly, HLA class II alleles that are rare in Caucasoids but common in other populations can be assessed for their contributory role in IDDM. Secondly, the different HLA class II gene linkage arrangements in different populations can help map the IDDM susceptibility determinants. This chapter reviews studies of HLA class II associations with IDDM in Asian Indians, Chinese, Japanese, Africans and black Americans. Most of these studies have been based on HLA-DR serology. However, DNA analyses, based on restriction fragment length polymorphism, sequence specific oligonucleotide hybridizations of polymerase chain reaction products and DNA sequencing, have made clear the identity of genes contributing to susceptibility or resistance to IDDM in populations of non-Caucasoid origin. DNA sequence analysis of the variable regions of the HLA-DQA, DQB and DRB genes has revealed at least eight alleles at HLA-DQA, 13 at HLA-DQB and 34 at HLA-DRB1. This chapter correlates HLA-DR and DQ allelic diversity with inherited predisposition to IDDM on a global basis. IDDM is strongly associated with the serological specificities of HLA-DQ, rather than with particular amino acid substitutions in class II alleles. DQw8 has a high risk for IDDM, DQw4, DQw5 and DQw9 have a lesser risk, while DQw6 and DQw7 are protective in IDDM. DQw2 is permissive for IDDM, depending on the presence of other HLA class II alleles. Increased heterozygosity at HLA is observed in Oriental patients, as it is in Caucasoid IDDM patients. The nature of this synergism is examined in terms of possible interactive effects between DQA and DQB alleles or DRB and DQB alleles; both effects could be operating. The conclusion from this genetic analysis is that molecular mimicry at HLA-DQ, with either foreign or autoantigens, may be an important mechanism in IDDM. Additionally, the anomalous role of DQw2 in IDDM suggests that a further mechanism, such as T cell activation, may control the ability to mount an immune response against autoantigens. Further studies, possibly with transfectant cell lines, are necessary to clarify the functional role of HLA class II genes in IDDM.
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PMID:Cross-ethnic group comparisons of HLA class II alleles and insulin dependent diabetes mellitus. 189 68

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.
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PMID:HLA-DQ and TAP2 genes in patients with insulin-dependent diabetes mellitus. 800 38

We examined HLA Class II antigens in 116 Japanese IDDM patients [84 typical IDDM (T-IDD); 32 slowly progressive IDDM (S-IDD)] by the hybridization protection assay (HPA) which is a novel HLA typing method based on hybridization of acridinium-ester-labeled DNA probes to amplified DNA. We detected HLA-DRB1, -DQA1 and -DQB1 genes by this method which is capable of analyzing over 50 samples within 4 h with high sensitivity. Positive associations were found in DRB1*0405, DRB1*0802, DRB1*0901, DQA1*0301, DQB1*0303 and DQB1*0401, negative correlations in DRB1*0403, DR2, DR12, DRB1*0801 or 03, DQA1*0101 or 02, DQA1*0501, DQB1*0301 and DQB1*0602 alleles. The absence of aspartic acid (Asp) at position 57 of the DRB1 chain and the presence of arginine (Arg) at position 52 of the DQA1 chain correlated positively with both types of IDDM. There were no significant differences in HLA between T-IDD and S-IDD. These results suggest that the absence of Asp at position 57 of the DRB1 chain and the presence of Arg at position 52 of the DQA1 chain are significant Japanese IDDM patients and that DRB1*0802, in which the amino acid at position 57 is aspartic acid, may play a role in the pathogenesis of IDDM. Also, T-IDD and S-IDD have common bases in the HLA gene.
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PMID:Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay. 807 Mar 5

HLA-DRB1 and -DQB1 genes were analyzed in 98 Chinese IDDM patients and 205 control subjects from Taiwan. The DRB1*0301-DQB1*0201 haplotype conferred strong susceptibility (RR = 7.7, pc < 10(-5)). DRB1*0405 also conferred susceptibility (RR = 3.1, Pc < 0.0005) whereas DRB1*0403 (RR = 0.7) and DRB1*0406 (RR = 0.2) conferred protection. Indeed, the relative risk for the DRB1*0405-DQB1*0302 haplotype (RR = 33.7, Pc < 0.002) was 48 and 168 times higher than those conferred by the DRB1*0403-DQB1*0302 and DRB1*0406-DQB1*0302 haplotypes, respectively, suggesting that the protection conferred by DRB1*0403 and 0406 is dominant over DQB1*0302. The strong linkage disequilibrium observed between DQB1*0302 and DRB1*0403(0406) can thus explain the surprising finding that the frequency of DQB1*0302 was not significantly increased in the Chinese IDDM patients (RR = 0.9). Because the DRB1*0405-DQB1*0302 haplotype (RR = 33.7) conferred higher susceptibility than the DRB1*0405-DQB1*0401 (RR = 2.5) or DRB1*0405-DQB1*0301 (RR = 2.1) haplotypes, DQB1*0302 is indeed a susceptibility factor, while both DQB1*0301 and DQB1*0401 may confer protection against IDDM. The increased frequency of the protective DQB1*0401 allele in patients compared to controls is due to linkage disequilibrium between DRB1*0405 and DQB1*0401. Interestingly, the previously demonstrated protective effect of DQB1*0602 was not very strong in the Chinese (RR = 0.4). Our results suggested that HLA-encoded susceptibility to IDDM is determined by the combined effects of all DR and DQ molecules present in an individual. Therefore, the genotypic combinations of DR and DQ genes as well as their linkage disequilibria can influence IDDM susceptibility. At least four DR and DQ molecules conferring high susceptibility (DRB1*0301, DRB1*0405, and DQ alpha/beta 0301/0201 and 0301/0302) occur at high frequency in the Chinese population. However, linkage disequilibria between highly susceptible DR and protective DQ or vice versa (e.g., DRB1*0405-DQB1*0301[0401] and DRB1*0403[0406]-DQB1*0302) are probably responsible for the lower incidence of IDDM in the Chinese.
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PMID:HLA-encoded susceptibility to insulin-dependent diabetes mellitus is determined by DR and DQ genes as well as their linkage disequilibria in a Chinese population. 877 Jun 34

HLA class II polymorphism in Moroccan IDDM patients has not been investigated so far. In this study, HLA-DRB1, -DQA1, and -DQB1 allele and haplotype frequencies were analyzed in 125 unrelated Moroccan IDDM patients and 93 unrelated healthy controls, all originating from the Souss region and mostly of Berber origin. Some common features with other Caucasian groups were observed, in particular, a predisposing effect of the DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 alleles or allelic combinations. The Moroccan IDDM group also presented with more specific characteristics. Among DRB1*04 subtypes, DRB1*0405 was associated with susceptibility to and DRB1*0406 with protection from the disease. The haplotype and the relative predispositional effect (RPE) analyses indicated that the DRB1*08-DQA1*0401-DQB1*0402 haplotype was also associated with susceptibility to IDDM. Interestingly, the DRB1*09-DQA1*0301-DQB1*0201 haplotype, completely absent from the control group and very rare in North African populations, was observed in 7.2% of the Moroccan diabetics. Conversely, the DRB1*07-DQA1*0201-DQB1*0201 and DRB1*15-DQA1*0102-DQB1*0602 haplotypes were associated with protection from IDDM. Finally, we observed an age-dependent genetic heterogeneity of IDDM, the frequencies of predisposing alleles being higher and those of protective alleles lower in childhood- than in adult-onset diabetics. Our data on Moroccan diabetics, together with data on European and Northern Mediterranean patients, suggest a gradient of various HLA class II predisposing and protective markers that link these populations.
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PMID:Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics. 887 68

The T-cell receptor beta locus (TCRB) on chromosome 7q35 was studied as a candidate region for genetic susceptibility to type 1 insulin-dependent diabetes (IDDM). A highly polymorphic microsatellite marker mapping to the TCRBV6.7 gene and a TCRB C-region RFLP were used to genotype the members of a total of 21 multiplex IDDM families from two different geographical areas. There was no evidence to support linkage to either of these markers with IDDM, and conventional two-point analysis excluded linkage to the telomeric end of the TCRB complex, in the region of the highly informative TCRBV6.7 marker. There was significant linkage of IDDM to the class II HLA-D locus with significant lod scores > 3.0 obtained for the HLA-DRB1 and HLA-DQB1 genes. Affected sib-pair (ASP) and transmission disequilibrium (TDT) association tests confirmed these findings.
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PMID:No linkage or association of telomeric and centromeric T-cell receptor beta-chain markers with susceptibility to type 1 insulin-dependent diabetes in HLA-DR4 multiplex families. 890 43

MHC class II genes play an important role in the autoimmune destruction of the pancreatic b-cell occurring in IDDM. The genetic pattern of the disease was investigated in Mexican Mestizos. The serological findings of HLA antigens showed a significant association of DR3, DR4, DQ2 and DQ8 and a protective effect of DR11, DR15, DQ5, DQ6 and DQ7. With these results, DNA analysis of HLA-DRB1, B3, B4, DQA1, DQB1, DPA1, DPB1 genes was performed using PCR with allele specific oligotyping. Among the patients, 92.78 carry DQA1 alleles that have ARG in position 52 of DQa chain, and 78.2% are ASP- in DQ5-57. The RR for homozygotes is 32.8 and 5.6, respectively. The main haplotype involved is DRB1*0405, DQA1*0301, DQB1*0302. Thus, DQa and DQb form a relevant recognition site for the "diabetogenic peptidett which induces the autoimmune destruction. Positions 57 and 74 of DRB1 locus contribute highly to the expression and severity of IDDM in Mestizos and other ethnic groups, but not in Caucasians or Blacks.
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PMID:[MHC-dependent molecular mechanisms of susceptibility and protection in type I diabetes in Mexicans]. 894 98

Results from a recent study suggested that polymorphisms within the HLA class II genes LMP2 and LMP7 were associated with the susceptibility for developing IDDM, and that this association could not be explained by linkage disequilibrium to HLA-DR or -DQ genes. We typed 285 IDDM patients and 337 HLA-DRB1-DQA1-DQB1 genotypically matched control subjects from an ethnically homogeneous population for both the G/T polymorphism in intron 6 of the LMP7 gene and the Arg-His polymorphism in the LMP2 gene. In addition, we typed IDDM families in which at least one parent was homozygous for a DRB1-DQA1-DQB1 haplotype and performed a transmission/disequilibrium test of these LMP polymorphisms. Our data suggest that none of these LMP2 or LMP7 polymorphisms are independently associated with IDDM susceptibility, in contrast to what has been previously reported by others. Further, our results suggest that one partial explanation for the previously reported independent association between IDDM and these LMP polymorphisms may have been that patients and control subjects were not matched for DRB1*04 subtypes. Our results emphasize the need for a complete matching for DRB1, DQA1, and DQB1 alleles between patients and control subjects when attempting to detect independent effects of other polymorphisms in the HLA complex on IDDM susceptibility or protection.
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PMID:No independent associations of LMP2 and LMP7 polymorphisms with susceptibility to develop IDDM. 900 Jul 9

HLA-DRB1, DQA1 and DQB1 alleles have been determined in 42 families with one IDDM proband and 64 healthy controls, by oligotyping (PCR-SSO) using primers and probes from the XI International Histocompatibility Workshop. A positive DRB1*03 and DRB1*04 association with the disease was observed, whereas DRB1*11 and DRB1*07 showed negative association but 19% of patients carried DRB1 alleles different to DRB1*03 or *04. When single alleles were considered, DQA1*03 showed the strongest association with susceptibility to the disease (RR = 8.2, Pc = 0.00001) but this association was outgrown by 2 and 3 allele combinations, with genotype DRB1*04-DQA1*03-DQB1*0302/DRB1*03- DQA1*0501- DQB1*0201 showing the strongest association (RR = 28, Pc = 0.002). Application of the relative predispositional effect (RPE) method to our data, revealed a further susceptibility risk provided by the DRB1*13-DQA1*0102-DQB1*0604 haplotype once DR3 and DR4 haplotypes were removed. When DQA1-DQB1 genotypes were analysed for presence of Arg 52 (DQ alpha) and absence of Asp 57 (DQ beta), genotypes SS/SS were found significantly increased in diabetics. Interestingly, one of the strongest associations with the disease was observed with the DQA1*03-DQB1*0201 combination encoded mainly by genes in trans (RR = 11.7 Pc = 0.00004). These observations and their comparison with DR-DQ haplotypes in more homogeneous ethnic groups support the stronger influence of the DQ molecule rather than the individual DR or DQ alleles in the susceptibility to IDDM. They also emphasize the need for detailed HLA haplotype studies in non-Caucasian and ethnically mixed populations to gain further insight into the nature of genetic and environmental factors contribution to autoimmunity.
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PMID:HLA-DQA1 and DQB1 allele and genotype contribution to IDDM susceptibility in an ethnically mixed population. 909 50

Japanese IDDM patients have been demonstrated to have unique and different HLA associations from white patients. To elucidate the effect of HLA-associated genetic factors on the clinical heterogeneity of IDDM in Japanese people, HLA-DRB1, DQA1, and DQB1 genotypes in 88 childhood-onset Japanese IDDM patients were examined by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) or sequence-specific primers (SSP). Of the 88 IDDM patients, 26 (29.5%) had DRB1*0405-DQA1*0302-DQB1*0401/X (DR4-DQ4/X), 38 (43.2%) had DRB1*0901-DQA1*0302-DQB1*0303/X (DR9-DQ9/X), and 9 (10.2%) were DR4/9-DQ4/9 heterozygous in the present study (X does not contain protective alleles). Clinical heterogeneity such as age distribution at onset, prevalence and serum level of anti-GAD antibodies (GADAb), and residual pancreatic beta-cell function after diagnosis were compared between patients with HLA-DR4-DQ4 and DR9-DQ9. The frequency of DR9-DQ9 genotype was significantly higher in the younger (0-10 years) than in the older (11-16 years) age-group of onset, but the frequency of DR4-DQ4 was higher in the older (11-16 years) age-group. Although no association of DR-DQ genotypes with the prevalence and serum level of GADAb was found among newly diagnosed patients, long-standing DR9-DQ9 patients had significantly higher levels of GADAb than those with DR4-DQ4. While no difference in time course of serum C-peptide (CPR) levels was detected between GADAb+ and GADAb- patients, a remarkable difference was demonstrated between DR9-DQ9 and DR4-DQ4 patients. The residual pancreatic beta-cell function was retained more in patients with DR4-DQ4 than in those with DR9-DQ9 at diagnosis through 12-18 months after diagnosis. These results suggest that the DR9-DQ9 genotype may induce stronger autoimmune destructive response (T-helper 1 function) against target beta-cells than the DR4-DQ4 genotype does. Our findings may warrant further studies on the association of diabetogenic autoimmune response with HLA class II molecules and contribute to a clarification of interracial differences in HLA-encoded susceptibility to IDDM.
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PMID:Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children. 935 42


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