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

Abstract

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.

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References

  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)

    Article  ADS  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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. 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)

    Article  CAS  PubMed  Google Scholar 

  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)

    CAS  PubMed  PubMed Central  Google Scholar 

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

    MATH  Google Scholar 

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

  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)

    Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  Google Scholar 

  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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

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

    MATH  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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 1

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

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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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Nejentsev, S., Howson, J., Walker, N. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887–892 (2007). https://doi.org/10.1038/nature06406

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