Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) are strongly associated with alleles of HLA class II DR and DQ genes. We have studied HLA DRB1, DQA1, DQB1 allele and haplotype distribution in 152 IDDM children and 103 unrelated healthy individuals from the region of Lodz in central Poland by the polymerase chain reaction and hybridisation with allele-specific oligonucleotide probes. The DRB1*04 allele showed the strongest association with IDDM in the Polish population (OR = 3.87). The DRB1*03 allele was also associated with predisposition to the disease (OR = 3.25), particularly in DR3/4 heterozygous individuals (OR = 14.47). Among DR4 subtypes, DRB1*0401 was the most frequent both in patients and controls, whereas DRB1*0403 was rarely observed in patients and conferred a significant protection from IDDM. The DRB1*04-DQA1*0301-DQB1*0302 haplotype conferred the highest risk to develop IDDM. The presence of DRB1*0401 on this haplotype reinforced the disease risk whereas DRB1*0403 had a dominant protective effect even in the presence of the predisposing DQB1*0302 allele (OR = 0.24). The DRB1*1501-DQA1*0102-DQB1*0602 haplotype conferred a dominant protective effect (OR = 0.04). The different behaviour of the DRB1*04-DQB1*0302 haplotypes in conferring IDDM risk confirms that DRB1 by itself is strongly associated with IDDM independently from DQB1, with DRB1*0401 being a high frequency/moderate risk allele, and DRB1*0403 a high frequency/low risk allele in the Polish population.
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PMID:HLA class II-associated predisposition to insulin-dependent diabetes mellitus in a Polish population. 968 95

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is strongly associated with particular HLA class II alleles. However, non-HLA genetic factors are likely to be required for the development of the disease. The candidate genes include the cytoxic T-lymphocyte associated-4 (CTLA-4) gene located on chromosome 2q33, which encodes a cell surface molecule providing a negative signal for T-cell activation. We investigated CTLA-4 exon 1 polymorphism (position 49 A/G) in 192 IDDM children and 136 healthy controls from Central Poland, using allele-specific hybridisation. The CTLA-4/G allele was found on 56.0% of chromosomes in IDDM patients as compared to 43.4% in controls (p = 0.002), mostly in homozygous form (31.2% in patients vs 15.4% in controls, p = 0.002). This difference was even more pronounced in non-DRB1*03/non-DRB1*04 IDDM patients (G/G genotype frequency: 35.0% of IDDM patients vs 12.3% of controls, p = 0.04). Our data indicate that CTLA-4 exon 1 position 49 A/G dimorphism was significantly associated with predisposition to IDDM in our Central Poland population, particularly in patients lacking the strongly predisposing DRB1 alleles.
Diabetes Metab 1998 Jun
PMID:CTLA-4 gene polymorphism is associated with predisposition to IDDM in a population from central Poland. 969 57

Melioidosis is an important infectious disease of southeast Asia caused by an intracellular bacterium, Burkholderia pseudomallei. Cellular immunity is postulated to play important roles in immunity to melioidosis that may influence the severity and clinical outcome of the disease. The present study was undertaken to investigate possible associations of melioidosis with HLA class II alleles. HLA typing of HLA-DRB1, -DQA1, and -DQB1 was performed using polymerase chain reaction and sequence-specific oligonucleotide hybridization (PCR-SSO). Seventy-nine melioidosis patients and 105 healthy, ethnically and geographically matched controls were studied. Among 24 DRB1 alleles, 7 DQA1 alleles, and 13 DQB1 alleles identified in this population, an association with melioidosis was observed with DRB1*1602 which was increased in melioidosis patients (10.1%) compared to normal controls (4.8%), p = 0.047 (odds ratio (OR) = 2.25). In addition, significant increase of DRB1*1602 allele frequency and decrease of DQA1*03 were also observed in septicemic melioidosis patients, the most severe form of the disease (p = 0.01, OR = 3.10; and p = 0.047, respectively). Furthermore, a trend of association of DRB1*0701, DQA1*0201, and DQB1*0201 with relapse cases of melioidosis was also noted. In contrast, no HLA association was observed in localized melioidosis or melioidosis with diabetes mellitus. These findings provide the suggestive evidence of an immunogenetic basis of certain aspects of melioidosis.
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PMID:HLA-DR and -DQ associations with melioidosis. 975 14

We report on the role of HLA-DQA1 and DQB1 alleles in determining susceptibility to insulin-dependent diabetes mellitus (IDDM) in Hong Kong Chinese and investigate whether these alleles affect the age of onset of the disease. We studied 76 unrelated Chinese patients and 250 controls. There was no apparent predisposing effect of non-aspartic acid residues at position 57 of the DQ beta chain (Asp57-) but there was an excess of homozygous genotypes containing arginine at position 52 of the DQ alpha chain (Arg52+). This excess was mainly attributable to the genotype DQA1*0301/DQA1*05011 in early-onset disease. There was a significant excess of heterodimers of DQ alpha and DQ beta carrying Arg52+ and Asp57- in both early-onset and late-onset disease, but the excess in early-onset disease was mainly attributable to a single heterodimer formed by DQA1*05011 and DQB1*0201. Of three DQA1/DQB1 genotypes containing a double dose of Arg52+ and Asp57-, only one had a strong association with both early-onset and late-onset disease. We show that early-onset IDDM and late-onset IDDM in Chinese may be separated on the basis of their associated DQA1 and DQB1 genotypes and we conclude that previously reported associations of IDDM with Arg52+ and Asp57- residues in Chinese are secondary to specific combinations of DQA1 and DQB1 alleles. We also show that DRB1 molecules play a distinct role in determining susceptibility to early-onset IDDM but the greatest effect is exerted by specific DR/DQ genotypic combinations.
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PMID:Strong association between DQA1/DQB1 genotype and early-onset IDDM in Chinese: the association is with alleles rather than specific residues. 977 26

The association of HLA-DRB1 and DQB1 genes with IDDM in Koreans was assessed using 115 IDDM patients and 140 nondiabetic controls. DQB1*0201 is the only DQB1 allele positively associated with IDDM while DQB*0602, *0601 and *0301 are negatively associated. Three DRB1 alleles (DRB1*0301, DRB1*0407 and DRB1*0901) are positively associated while four DR allele groups (DRB1*15, DRB1*12, DRB1*10 and DRB1*14) are negatively associated. However, Haplotype analyses indicated that DQB1*0302, DRB1*0405 and DRB1*0401 may confer susceptibility because the DRB1*0405-DQB*0302 and DRB1*0401-DQB1*0302 haplotypes are positively associated with the disease. The lack of association in Koreans with the DQB1*0302 allele, which appears predisposing in studies of non-Orientals, is due to its strong linkage disequilibrium (LD) with the protective DRB1*0403 and *0406 alleles, while the lack of association with DRB1*0405 is because of its strong LD with the protective DQB1*0401 allele. Nine DR/DQ genotypes confer significantly increased risk to IDDM. Seven of the nine genotypes (DR3/4s, DR1/4s, DR4s/13, DR4s/8, DR4s/7, DR9/13 and DR3/9) were also found to be at high risk to IDDM in other populations, while the two others (DR1/9 and DR9/9) are only found in Koreans. Surprisingly, DR4/4 homozygotes are not associated with high risk to IDDM in Koreans. This observation can be explained by the high frequency of protective DR4 subtypes and the protective DQ alleles (0301 and 0401) associated with the susceptible DR4 alleles. Our analyses indicate that the counterbalancing act between susceptible DRB1 and protective DQB1, and vice versa, that has already been observed in Chinese and Japanese, is the major factor responsible for the low incidence of diabetes in Koreans.
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PMID:Combinations of HLA DR and DQ molecules determine the susceptibility to insulin-dependent diabetes mellitus in Koreans. 983 Nov 35

The high incidence of insulin-dependent diabetes mellitus (IDDM) in Finland contrasts strikingly with the low rates in the neighbouring populations of countries in the Eastern Baltic region: Estonia, Latvia and Russia. To evaluate the possible contribution of genetic factors to these differences, the frequencies of HLA-DQB1 alleles and relevant DQB1-DQA1 or DQB1-DRB1 haplotypes associated with IDDM risk or protection were analysed among IDDM patients and control subjects from these four populations. An increased frequency of HLA-DQB1*0302, DQB1*02-DQA1*05 and DQB1*0302-DRB1*0401 was observed in subjects with IDDM in all studied populations, whereas the prevalence of DQB1*0301 and DQB1*0602 and/or *0603 was decreased among patients. The degree of IDDM risk associated with HLA alleles analysed here did not differ significantly between the populations. Comparisons of the distribution of IDDM-related HLA alleles and haplotypes in the background populations revealed its consonance with IDDM incidence. The combined frequency of high risk genotypes was significantly higher among Finns than in other populations studied. Our data support the hypothesis that variance in the dispersion of HLA alleles is the genetic basis of variation of IDDM incidence observed in the Eastern Baltic region.
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PMID:Distribution of insulin-dependent diabetes mellitus (IDDM)-related HLA alleles correlates with the difference in IDDM incidence in four populations of the Eastern Baltic region. 986 37

Of 957 patients with type 1 diabetes without known Addison's disease 1.6% (n = 15) were positive for 21-hydroxylase autoantibodies. Among DQ8/DQ2 heterozygous patients, the percentage expressing 21-hydroxylase autoantibodies was 5% (10 of 208) vs. less than 0.5% of patients with neither DQ8 nor DQ2. Three of the diabetic patients found to have 21-hydroxylase autoantibodies on screening were subsequently diagnosed with Addison's disease. Overall, the genotype DQ8/DQ2, consisting of DRB1*0404/DQ8 with DRB1*0301/DQ2, was present in 14 of 21 patients with Addison's disease (8 of 12 with diabetes and 6 of 9 without diabetes or antiislet autoantibodies) vs. 0.7% of the general population (109 of 15,547; P < 10(-6)) and 11% of patients with DM without Addison's disease (62 of 578; P < 10(-6)). Among patients with diabetes with DQ8, Addison's disease was strongly associated with the specific DRB1 subtype, DRB1*0404 (8 of 9 patients from 8 families, in contrast to only 109 of 408 DQ8 DM patients with diabetes without Addison's disease having DRB1*0404; P < 0.001). Among 21-hydroxylase autoantibody-positive DQ8 patients, 80% with DRB1*0404 (12 of 15) had Addison's disease, in contrast to 1 of 10 autoantibody-positive patients with DRB1*0401 or DRB1*0402 (P < 0.001). We conclude that patients with DRB1*0404 and 21-hydroxylase autoantibodies are at high risk for Addison's disease. Patients with DRB1*0401 and DRB1*0402 have more limited progression to Addison's disease despite the presence of 21-hydroxylase autoantibodies.
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PMID:DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease. 992 Jan 3

Thirty-four insulin-dependent diabetes mellitus (IDDM) patients from North India were studied with respect to their HLA class II alleles including those of the DRB1, DQA1, DQB1 and DPB1 loci, using the polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes (SSOP). They were compared with the class II alleles of 94 normal adult controls from the same ethnic background. The results show a statistically significant increase of DRB1*03011 (p < 0.00001), DQB1*0201 (p < 0.007), DQA1*0501 (0.0027) and DPB1*2601 (p < 0.0042) in patients compared to controls. DR*04 was not significantly increased. However, homozygosity for DRB1*03011 was increased more than expected. DRB1*1501 and *1502 did not show a significant decrease in the patients. However, DRB1*0701 was decreased significantly, but this difference did not remain significant when the p value was corrected for the number of alleles tested. Similarly, DPB1*2601 was increased significantly in the patients but did not remain significant after p was corrected for the number of alleles tested. However, DPB1*2601 was increased, and remained significant after correction, in patients not having HLA-DR3. We also studied the possible role of aspartic acid at codon 57 of the DQ beta chain in protection against development of diabetes, and arginine at codon 52 of the DQ alpha chain in susceptibility. We observed an increase in non-Asp57 alleles in DQ beta and Arg52 in DQ alpha in the patients, however, this effect seems to be due to the fact that the most prevalent haplotype in diabetic patients: DRB1*03011-DQA1*0501-DQB1*0201, has DQB1 and DQA1 alleles which carry non-Asp57 and Arg52, respectively.
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PMID:Associations of MHC class II alleles with insulin-dependent diabetes mellitus (IDDM) in patients from North India. 1040 2

In this study, we report type 1 diabetes age-of-onset association with HLA class II (DRB1, DQB1, and DPB1) and class I (A) genes in 222 multiplex families from the Human Biological Data Interchange. Linear regression showed a small (R2 = 0.26) but significant correlation in the ages of onset among sib pairs. A strong association in age of onset between members of sib pairs was observed when the analysis was performed using contingency tables that split sibs into three age-at-onset ranges (0-10, 11-20, and 21-36 years). The association is strongest for sib pairs that share both haplotypes and is nonsignificant for sib pairs that do not share any DR-DQ haplotypes. A goodness-of-fit test revealed that DR-DQ haplotype sharing cannot account for all the association in age of onset among sib pairs. The age-of-onset distribution of DR-DQ haplotypes is affected by the DPB1 and A alleles present. The strongest associations were found with the A locus: DR3/DR4 genotype frequency decreases with age of onset in this data set only among A*0101- individuals, and A*2402 is strongly associated with younger age of onset in many DR-DQ haplotypes.
Diabetes 1999 Aug
PMID:Association between type 1 diabetes age of onset and HLA among sibling pairs. 1042 87

With a view to establishing an accurate evaluation of the genetic predisposition to insulin-dependent type I diabetes (IDDM), we have built a model based on the characteristics of the relevant pockets of HLA-DR and -DQ molecules. Three independent populations were investigated. Group I and group II were Caucasoids, while group III was Japanese, including a total of 1,166 IDDM patients and 2,391 healthy controls. We formulate the hypothesis that suceptibility to IDDM is not only explained by the absence of Aspartate 57 (negative charge) from pocket 9 of DQB1 (P9DQ), but also by the presence of an electric charge (+/- vs. neutral), generated by residues 70, 71 and 74 in pockets 4 of DRB1 (P4DR) and DQB1 (P4DQ) molecules. The respective weight of each pocket, was evaluated in a multivariate analysis based on the logistic regression method. The 4 components (2 loci and 2 pockets) were systematically analysed in the computer model. It was clearly shown that the structural characteristics of pockets P9DQ-P4DR and, to a lesser degree that of P4DQ, account for IDDM predisposition. On applying the model to the whole international series, it appears that the highest risk concerns individuals with P9DQ non-Asp 57 and both the charged P4 of DRB1 and P4 of DQB1, conferring a 80% prediction of susceptibility. Conversely, P9DQ Asp and neutral P4DR and P4DQ give the lowest risk with a predictive value of 5%. This model of risk susceptibility prediction fits remarkably well with the observed distribution in a worldwide study. It allows a better evaluation of the respective role of HLA-DR and -DQ molecules as a major component of susceptibility to IDDM.
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PMID:A new predictive model for insulin-dependent diabetes mellitus susceptibility based on combinations of molecular HLA-DRB1 and HLA-DQB1 pockets. 1055 17


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