Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887-892

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.
Nature (Impact Factor: 41.46). 11/2007; 450(7171):887-892. DOI: 10.1038/nature06406


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; 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, 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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Available from: Alexandra S Whale, Dec 12, 2014
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    • "contribute to development of diabetes (Katz et al. 1993, Serreze et al. 1994, Wicker et al. 1994, Serreze et al. 1997, Jarchum et al. 2007, Nejentsev et al. 2007,Tsai et al. 2008). "
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    • "Simulations involved estimating h2 for subsets of cases and controls from a Type I Diabetes (T1D) dataset. We choose to use a T1D because the histocompatibility complex (MHC) region on chromosome 6 has major genetic contribution to risks of both DILI2 and T1D1118. Specifically, we used the Welcome Trust Case Control Consortium (WTCCC) T1D dataset (1963 cases and 2938 controls)18. "
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    • "Specifically, the KIR3DL1 protein is known to interact with the HLA class I allotypes that contain the HLA-Bw4 serological epitope [2,3], whereas the protein encoded by KIR3DS1, which shares 97% sequence similarity to KIR3DL1, is thought to bind the more restrictive HLA-Bw4-80I epitope subset [4]. The grouping of HLA-A and HLA-B alleles according to HLA-Bw4 serological epitope [5] is given in Additional file 1: Table S1 and includes several HLA class I alleles which are associated with T1D risk after conditioning on the major HLA class II effects [6,7]. To date, KIR3DL1/3DS1 association with T1D has only been studied using qPCR assays in limited sample sizes, which assess presence or absence of each KIR gene [8]. "
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