1. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK
2. MRC Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge, CB10 1SB, UK
3. Department of Physiology Anatomy and Genetics, University of Oxford, OX1 3QX, UK
4. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.
5. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
6. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
7. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
8. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
9. The Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.
10. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
11. Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.
12. National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge CB2 2PT, UK.
13. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
14. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
15. Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
16. National Health Service Blood and Transplant, Sheffield Centre, Longley Lane, Sheffield S5 7JN, UK.
17. National Health Service Blood and Transplant, Brentwood Centre, Crescent Drive, Brentwood CM15 8DP, UK.
18. The Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun CF72 9WB, UK.
19. The Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh EH17 7QT, UK.
20. National Health Service Blood and Transplant, Southampton Centre, Coxford Road, Southampton SO16 5AF, UK.
21. Avon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.
22. Division of Community Health Services, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
23. Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
24. University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
25. Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.
26. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
27. SGDP, The Institute of Psychiatry, King's College London, De Crespigny Park Denmark Hill, London SE5 8AF, UK.
28. School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
29. LIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.
30. IBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
31. Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
32. Department of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
33. Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK.
34. Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.
35. Department of Gastroenterology & Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
36. Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.
37. Medicine and Therapeutics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Grampian AB9 2ZB, UK.
38. Clinical Pharmacology Unit and the Diabetes and Inflammation Laboratory, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
39. Centre National de Genotypage, 2, Rue Gaston Cremieux, Evry, Paris 91057, France.
40. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
41. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.
42. Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
43. arc Epidemiology Research Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
44. Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
45. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.
46. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DU, UK.
47. Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK.
48. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
49. The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Road, Bristol BS2 8PR, UK.
50. MRC Laboratories, Fajara, The Gambia.
51. Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland 4102, Australia.
52. Botnar Research Centre, University of Oxford, Headington, Oxford OX3 7BN, UK.
53. Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
54. Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
55. Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
56. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. †Present address: Illumina Cambridge, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex CB10 1XL, UK.
57. These authors contributed equally to this work.
58. Lists of participants and affiliations appear at the end of the paper.

Correspondence to: Joanna M. M. Howson^1,57 Correspondence and requests for materials should be addressed to J.M.M.H. Email: Joanna.Howson@cimr.cam.ac.uk.

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 region^{4, 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; P_combined = 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 studies^{4, 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.

1. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, CB2 0XY, UK
2. MRC Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge, CB10 1SB, UK
3. Department of Physiology Anatomy and Genetics, University of Oxford, OX1 3QX, UK
4. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.
5. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
6. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
7. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
8. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
9. The Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.
10. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
11. Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.
12. National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge CB2 2PT, UK.
13. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
14. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
15. Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
16. National Health Service Blood and Transplant, Sheffield Centre, Longley Lane, Sheffield S5 7JN, UK.
17. National Health Service Blood and Transplant, Brentwood Centre, Crescent Drive, Brentwood CM15 8DP, UK.
18. The Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun CF72 9WB, UK.
19. The Scottish National Blood Transfusion Service, Ellen's Glen Road, Edinburgh EH17 7QT, UK.
20. National Health Service Blood and Transplant, Southampton Centre, Coxford Road, Southampton SO16 5AF, UK.
21. Avon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.
22. Division of Community Health Services, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
23. Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
24. University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
25. Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.
26. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
27. SGDP, The Institute of Psychiatry, King's College London, De Crespigny Park Denmark Hill, London SE5 8AF, UK.
28. School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK.
29. LIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.
30. IBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.
31. Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
32. Department of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
33. Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK.
34. Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.
35. Department of Gastroenterology & Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
36. Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.
37. Medicine and Therapeutics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Grampian AB9 2ZB, UK.
38. Clinical Pharmacology Unit and the Diabetes and Inflammation Laboratory, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
39. Centre National de Genotypage, 2, Rue Gaston Cremieux, Evry, Paris 91057, France.
40. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
41. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.
42. Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
43. arc Epidemiology Research Unit, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
44. Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
45. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.
46. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DU, UK.
47. Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK.
48. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.
49. The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Road, Bristol BS2 8PR, UK.
50. MRC Laboratories, Fajara, The Gambia.
51. Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland 4102, Australia.
52. Botnar Research Centre, University of Oxford, Headington, Oxford OX3 7BN, UK.
53. Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
54. Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
55. Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
56. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. †Present address: Illumina Cambridge, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex CB10 1XL, UK.
57. These authors contributed equally to this work.
58. Lists of participants and affiliations appear at the end of the paper.

Correspondence to: Joanna M. M. Howson^1,57 Correspondence and requests for materials should be addressed to J.M.M.H. Email: Joanna.Howson@cimr.cam.ac.uk.

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