Dataset Information

The HLA-B 3906 allele imparts a high risk of diabetes only on specific HLA-DR/DQ haplotypes.

ABSTRACT:

Aims/hypothesis

We investigated the risk associated with HLA-B*39 alleles in the context of specific HLA-DR/DQ haplotypes.

Methods

We studied a readily available dataset from the Type 1 Diabetes Genetics Consortium that consists of 2,300 affected sibling pair families genotyped for both HLA alleles and 2,837 single nucleotide polymorphisms across the major histocompatibility complex region.

Results

The B*3906 allele significantly enhanced the risk of type 1 diabetes when present on specific HLA-DR/DQ haplotypes (DRB1 0801-DQB1 0402: p?=?1.6?×?10(-6), OR 25.4; DRB1 0101-DQB1 0501: p?=?4.9?×?10(-5), OR 10.3) but did not enhance the risk of DRB1 0401-DQB1 0302 haplotypes. In addition, the B 3901 allele enhanced risk on the DRB1 1601-DQB1 0502 haplotype (p?=?3.7?×?10(-3), OR 7.2).

Conclusions/interpretation

These associations indicate that the B 39 alleles significantly increase risk when present on specific HLA-DR/DQ haplotypes, and HLA-B typing in concert with specific HLA-DR/DQ genotypes should facilitate genetic prediction of type 1 diabetes, particularly in a research setting.

SUBMITTER: Baschal EE

PROVIDER: S-EPMC3110277 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Publications

The HLA-B 3906 allele imparts a high risk of diabetes only on specific HLA-DR/DQ haplotypes.

Baschal E E EE Baker P R PR Eyring K R KR Siebert J C JC Jasinski J M JM Eisenbarth G S GS

Diabetologia 20110501 7

<h4>Aims/hypothesis</h4>We investigated the risk associated with HLA-B*39 alleles in the context of specific HLA-DR/DQ haplotypes.<h4>Methods</h4>We studied a readily available dataset from the Type 1 Diabetes Genetics Consortium that consists of 2,300 affected sibling pair families genotyped for both HLA alleles and 2,837 single nucleotide polymorphisms across the major histocompatibility complex region.<h4>Results</h4>The B*3906 allele significantly enhanced the risk of type 1 diabetes when pr ...[more]

PMID: 21533899

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Project description:ObjectiveThe Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes.Research design and methodsSix hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child.ResultsA number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR] 3.64) and the DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-DQA1*0301-DQB1*0302 haplotypes (ORs 11.37, 8.39, and 3.63), followed by the DRB1*0404-DQA1*0301-DQB1*0302 (OR 1.59) and the DRB1*0801-DQB1*0401-DQB1*0402 (OR 1.25) haplotypes. The most protective haplotypes are DRB1*1501-DQA1*0102-DQB1*0602 (OR 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR 0.02), and DRB1*0701-DQA1*0201-DQB1*0303 (OR 0.02).ConclusionsSpecific combinations of alleles at the DRB1, DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different type 1 diabetes risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and that the trans-complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.

Dataset Information

The HLA-B 3906 allele imparts a high risk of diabetes only on specific HLA-DR/DQ haplotypes.

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Publications

The HLA-B 3906 allele imparts a high risk of diabetes only on specific HLA-DR/DQ haplotypes.

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