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Cited by 790Diabetes and associated disordersGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk

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Erlich, Henry, Valdes, Ana Maria, Noble, Janelle, Carlson, Joyce A., Varney, Mike, Concannon, Pat, Mychaleckyj, Josyf C., Todd, John A. +6 more·2008·Diabetes
DOI 10.2337/db07-1331PMC PMC4103420
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Abstract

OBJECTIVE—The 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 METHODS:—Six 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. RESULTS—A 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). CONCLUSIONS—Specific 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.

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  • HLA class II show the strongest association with type 1 diabetes, where haplotypes DRB1*0401-DQB1*0302 and DRB1*0301-DQB1*0201 confer the greatest susceptibility, and DRB1*1501 and DQA1*0102-DQB1*0602 provide disease resistance.

    “Of the many HLA types, HLA class II show the strongest association with type 1 diabetes, where haplotypes DRB1*0401-DQB1*0302 and DRB1*0301-DQB1*0201 confer the greatest susceptibility, and DRB1*1501 and DQA1*0102-DQB1*0602 provide disease resistance.74”

    From Type 1 diabetes (2014) · cites this paper as [74]

    The Results (page not provided) place both named susceptibility haplotypes among the most susceptible and identify DRB1*1501-DQA1*0102-DQB1*0602 as highly protective. But DRB1*0405-DQA1*0301-DQB1*0302 has a higher reported odds ratio than either named susceptibility haplotype, so the claim that those two confer the greatest susceptibility overstates the risk ranking. The passages also do not compare the strength of class II associations with other HLA classes. (LLM, conf=0.86)

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Authors
Erlich, H., Valdes, A. M., Noble, J., Carlson, J. A., Varney, M., Concannon, P., Mychaleckyj, J. C., Todd, J. A., Bonella, P., Fear, A. L., Lavant, E., Louey, A., Moonsamy, P., & for the Type 1 Diabetes Genetics Consortium
Affiliations
  • Roche Molecular Systems, Alameda, California
  • Children's Hospital Oakland Research Institute, Oakland, California
  • Skåne University Hospital (SE)
  • Australian Red Cross Lifeblood (AU)
  • Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
  • University of Virginia (US)
  • University of Cambridge (GB)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2008-04-01
Volume
57
Issue
4
Pages
1084-1092
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db07-1331
PMC
PMC4103420
OpenAlex
W2157754662
Cited by
790
References
0
Citations by year
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FWCI
27.04
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Wellcome Trust
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK061722, U01DK062418)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
type 1 diabetes, HLA-DRB1, HLA-DQA1, HLA-DQB1, genetic susceptibility, protective haplotypes, family-based association, high-resolution HLA typing
MeSH terms
Child, Child, Preschool, Diabetes Mellitus, Type 1, Family, Female, Genotype, HLA-DQ Antigens, HLA-DR Antigens, Humans, Male, Risk Factors, Age of Onset, Genetic Predisposition to Disease, White People, Asian People, HLA-DRB1 Chains, HLA-DQ alpha-Chains, HLA-DQ beta-Chains

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