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

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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 region4,5,6,7,8,9,10,11. 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; Pcombined = 2.01 × 10-19 and 2.35 × 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 studies4,5,6,7,8,10,11,12,13,14,15,16 , 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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Figure 1: Association analyses across the MHC.
Figure 2: Association analyses of 1,475 SNPs across the MHC.


  1. 1

    Todd, J. A., Bell, J. I. & McDevitt, H. O. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987)

  2. 2

    Cucca, F. et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum. Mol. Genet. 10, 2025–2037 (2001)

  3. 3

    Todd, J. A. et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39, 857–864 (2007)

  4. 4

    Fennessy, M. et al. A gene in the HLA class I region contributes to susceptibility to IDDM in the Finnish population. Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia 37, 937–944 (1994)

  5. 5

    Nejentsev, S. et al. Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. Diabetes 49, 2217–2221 (2000)

  6. 6

    Lie, B. A. et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. Am. J. Hum. Genet. 64, 793–800 (1999)

  7. 7

    Valdes, A. M. et al. Extended DR3–D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians. Tissue Antigens 65, 115–119 (2005)

  8. 8

    Valdes, A. M., Erlich, H. A. & Noble, J. A. Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Hum. Immunol. 66, 301–313 (2005)

  9. 9

    Aly, T. A. et al. Extreme genetic risk for type 1A diabetes. Proc. Natl Acad. Sci. USA 103, 14074–14079 (2006)

  10. 10

    Noble, J. A. et al. The HLA class I A locus affects susceptibility to type 1 diabetes. Hum. Immunol. 63, 657–664 (2002)

  11. 11

    Honeyman, M. C., Harrison, L. C., Drummond, B., Colman, P. G. & Tait, B. D. Analysis of families at risk for insulin-dependent diabetes mellitus reveals that HLA antigens influence progression to clinical disease. Mol. Med. 1, 576–582 (1995)

  12. 12

    Wicker, L. S. et al. β2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 43, 500–504 (1994)

  13. 13

    Utsugi, T. et al. Major histocompatibility complex class I-restricted infiltration and destruction of pancreatic islets by NOD mouse-derived beta-cell cytotoxic CD8+ T-cell clones in vivo . Diabetes 45, 1121–1131 (1996)

  14. 14

    Marron, M. P., Graser, R. T., Chapman, H. D. & Serreze, D. V. Functional evidence for the mediation of diabetogenic T cell responses by HLA-A2.1 MHC class I molecules through transgenic expression in NOD mice. Proc. Natl Acad. Sci. USA 99, 13753–13758 (2002)

  15. 15

    Itoh, N. et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J. Clin. Invest. 92, 2313–2322 (1993)

  16. 16

    Foulis, A. K., Liddle, C. N., Farquharson, M. A., Richmond, J. A. & Weir, R. S. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29, 267–274 (1986)

  17. 17

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007)

  18. 18

    Herr, M. et al. Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21. Hum. Mol. Genet. 9, 1291–1301 (2000)

  19. 19

    Noble, J. A. et al. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am. J. Hum. Genet. 59, 1134–1148 (1996)

  20. 20

    Breiman, L., Friedman, J. H., Olshen, R. A. & Stone, C. J. Classification and Regression Trees (Wadsworth, Belmont, 1984)

  21. 21

    R Development Core Team. A Language and Environment for Statistical Computing. (R Foundation for statistical computing, Vienna, 2006)

  22. 22

    Therneau, T. M. & Atkinson, E. J. An Introduction to Recursive Partitioning Using the rpart Routine. Technical report no. 61 (Mayo Clinic, section of statistics, Minnesota, 1997)

  23. 23

    Roach, J. C. et al. Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden. Am. J. Hum. Genet. 79, 614–627 (2006)

  24. 24

    Aly, T. A. et al. High density SNP analysis of the MHC region reveals multiple loci for type 1A diabetes. Clin. Immunol. 123, S133 (2007)

  25. 25

    de Jersey, J. et al. Beta cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 104, 1295–1300 (2007)

  26. 26

    Poirot, L., Benoist, C. & Mathis, D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc. Natl Acad. Sci. USA 101, 8102–8107 (2004)

  27. 27

    Pinkse, G. G. et al. Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc. Natl Acad. Sci. USA 102, 18425–18430 (2005)

  28. 28

    Cordell, H. J. & Clayton, D. G. A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am. J. Hum. Genet. 70, 124–141 (2002)

  29. 29

    Stone, M. Cross-validation choice and assessment of statistical predictions. J. R. Stat. Soc. B 36, 111–147 (1974)

  30. 30

    Clayton, D. G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nature Genet. 37, 1243–1246 (2005)

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This work was funded by the Wellcome Trust and the Juvenile Diabetes Research Foundation International. We thank all of the patients, control subjects and family members for their participation. The Human Biological Data Interchange and Diabetes UK Warren repositories and UK GRID project are acknowledged for the collection of the type 1 diabetes patients and families. We acknowledge use of DNA from the British 1958 birth cohort collection (D. Strachan, S. Ring, W. McArdle, P. Burton, R. Jones and M. Pembrey), funded by the Medical Research Council and Wellcome Trust. S.N. is a Diabetes Research and Wellness Foundation Non-Clinical Fellow. R.D.C. and G.R. were funded by the Medical Research Council.

Author Contributions J.M.M.H performed all statistical data analyses, interpreted results, contributed to the direction of the study and wrote the manuscript. S.N. participated in the conception, design and coordination of the study, genotyping, data analysis and writing of the manuscript. J.A.T. participated in the conception, design and coordination of the study, as well as data analysis and writing of the manuscript. N.M.W. curated the data and helped coordinate the HLA typing. H.E.S. was responsible for DNA. J.S., S.F.F., P.R., M.H., E.K., J.M., J.H., L.M.M., D.S. and R.B. contributed to genotyping of SNPs, microsatellites and HLA loci. J.D.C. provided nsSNP GWA data. G.R. provided SNPs and genotyping in candidate genes from the MHC class III genes. R.D.C. provided SNPs in candidate genes from MHC class III genes. The Wellcome Trust Case Control Consortium provided GWA SNP data. D.G.C. gave guidance on statistical analyses.

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Correspondence to Joanna M. M. Howson.

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Supplementary information

Supplementary Information 1

The file contains Supplementary Results, Supplementary Discussion, Supplementary Methods, Supplementary Tables 1-7 and Supplementary Figure 1 with Legends (PDF 455 kb)

Supplementary Information 2

The file contains the list of members of The Biologics in RA Genetics and Genomics Study Syndicate (BRAGGS) Steering Committee and Breast Cancer Susceptibility Collaboration (UK) (PDF 33 kb)

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