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      HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes : Analysis of the Type 1 Diabetes Genetics Consortium Families

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          Abstract

          OBJECTIVE

          To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.

          RESEARCH DESIGN AND METHODS

          The frequency of DPA1 and DPB1 alleles and haplotypes in type 1 diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on HLA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined.

          RESULTS

          Eight DPA1 and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed; nineteen DPB1 alleles were associated with multiple DPA1 alleles. Following both analyses, type 1 diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes. Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype.

          CONCLUSIONS

          HLA DP allelic and haplotypic diversity contributes significantly to the risk for type 1 diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection. Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes.

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          Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A.

          Sergey Nejentsev, Joanna M M Howson, Neil M Walker … (2007)
          The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.
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            The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes.

            Kathleen M. Gillespie, Steven C Bain, Anthony H. Barnett … (2015)
            The incidence of childhood type 1 diabetes has risen over the past 50 years. We compared the frequency of HLA class II haplotypes in 194 patients diagnosed more than 50 years ago and 582 age-matched and sex-matched individuals diagnosed between 1985 and 2002. The proportion of high-risk susceptibility genotypes was increased in the earlier cohort (p=0.003), especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect.
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              The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes

              Spiros Fourlanos, Michael D. Varney, Brian Tait … (2008)
              OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades. RESEARCH DESIGN AND METHODS—Caucasoid subjects (n = 462) diagnosed with type 1 diabetes before age 18 between 1950 and 2005 were DRB1 genotyped. RESULTS—Mean ± SD age at diagnosis, 8.5 ± 4.5 years, did not differ across decades. Recent diagnosis was associated with a lower proportion but unchanged incidence of the highest-risk DRB1 genotype DR3,4 (2000–2005, 28% vs. 1950–1969, 79%; P < 0.0001) and a higher proportion of lower-risk genotypes DR4,X and DR3,X (2000–2005, 48% vs. 1950–1969, 20%; P = 0.0002). The frequency of the DRX,X genotype was low (≤3%) across decades. Recent birth was associated with a lower age at diagnosis for lower risk DR3,3 and DR4,4 (P < 0.0001) and DR4,X (P < 0.0001) and DR3,X (P = 0.015) genotypes but not for DR3,4. CONCLUSIONS—The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower-risk HLA class II genes, who previously would not have developed type 1 diabetes in childhood.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes
                Journal ID (hwp): diabetes
                Journal ID (pmc): diabetes
                Journal ID (publisher-id): Diabetes
                Title: Diabetes
                Publisher: American Diabetes Association
                ISSN (Print): 0012-1797
                ISSN (Electronic): 1939-327X
                Publication date (Print): August 2010
                Publication date (Electronic): 27 April 2010
                Volume: 59
                Issue: 8
                Pages: 2055-2062
                Affiliations
                [1] 1Victorian Transplantation & Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia;
                [2] 2Department of Twin Research, King's College London, London, UK;
                [3] 3Clinical Chemistry, University Hospital, Malmö, Sweden;
                [4] 4Children's Hospital Oakland Research Institute, Oakland, California;
                [5] 5Roche Molecular Systems, Alameda, California; and
                [6] 6Public Health Sciences, Bioinformatics & Genetics Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
                Author notes
                Corresponding author: Michael D. Varney, MVarney@ 123456arcbs.redcross.org.au .
                Article
                Publisher ID: 0680
                DOI: 10.2337/db09-0680
                PMC ID: 2911060
                PubMed ID: 20424227
                SO-VID: 350b777f-6007-44bb-a4a6-6a520c661654
                Copyright © © 2010 by the American Diabetes Association.
                License:

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                Date received : 6 May 2009
                Date accepted : 20 April 2010
                Categories
                Subject: Genetics

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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