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

Open access
The Wellcome Trust Case Control Consortium, Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A.·2007·Nature

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. 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 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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Metadata

Authors
The Wellcome Trust Case Control Consortium, Nejentsev, S., Howson, J. M. M., Walker, N. M., Szeszko, J., Field, S. F., Stevens, H. E., Reynolds, P., Hardy, M., King, E., Masters, J., Hulme, J., Maier, L. M., Smyth, D., Bailey, R., Cooper, J. D., Ribas, G., Campbell, R. D., Clayton, D. G., & Todd, J. A.
Venue
Nature
Published
2007-11-14
Volume
450
Issue
7171
Pages
887-892
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2066592806
Cited by
570
References
4
FWCI
25.29
Type
journal article
Language
en
Open access
bronze

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