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

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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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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

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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