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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    ABSTRACT: There is compelling evidence that autoreactive CD8+ T cells play a central role in precipitating the development of autoimmune diabetes in NOD mice, but the underlying mechanisms remain unclear. Given that CD103 recognizes an islet-restricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We show that CD103 is expressed by a discrete subset of CD8+ T cells that infiltrate pancreatic islets prior to the development of diabetes. Moreover, we demonstrate that diabetes development in CD103 deficient NODs is significantly delayed at early but not late time points suggesting that CD103 is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated wild type NODs beginning at 2weeks of age, through 5 weeks of age with a depleting anti-CD103 mAb and found a decreased incidence of diabetes following anti-CD103 mAb treatment compared to isotype control mAbs or non-depleting mAb to CD103. Moreover, a histologic examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These data indicate that CD103+ cells play a key role in the development of autoimmune diabetes, and are consistent with the hypothesis that CD103+CD8+ T effectors initiate the disease process.
    Journal of Endocrinology 12/2014; 224(3). DOI:10.1530/JOE-14-0396 · 3.72 Impact Factor
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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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    ABSTRACT: Recent genome-wide association studies identified certain human leukocyote antigen (HLA) alleles as the major risk factors of drug-induced liver injuries (DILI). While these alleles often cause large relative risk, their predictive values are quite low due to low prevalence of idiosyncratic DILI. Finding additional risk factors is important for precision medicine. However, optimal design of further genetic studies is hindered by uncertain overall heritability of DILI. This is a common problem for low-prevalence pharmacological traits, since it is difficult to obtain clinical outcome data in families. Here we estimated the heritability (h(2)) of DILI from case-control genome-wide single nucleotide polymorphism data using a method based on random effect models. We estimated the proportion of h(2) captured by common SNPs for DILI to be between 0.3 and 0.5. For co-amoxiclav induced DILI, chromosome 6 explained part of the heritability, indicating additional contributions from common variants yet to be found. We performed simulations to assess the robustness of the h(2) estimate with limited sample size under low prevelance, a condition typical to studies on idiosyncratic pharmacological traits. Our findings suggest that common variants outside of HLA contribute to DILI susceptability; therefore, it is valuable to conduct further GWAS with expanded case collection.
    Scientific Reports 07/2014; 4:5762. DOI:10.1038/srep05762 · 5.58 Impact Factor
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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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    ABSTRACT: Killer Immunoglobulin-like Receptors (KIRs) are surface receptors of natural killer cells that bind to their corresponding Human Leukocyte Antigen (HLA) class I ligands, making them interesting candidate genes for HLA-associated autoimmune diseases, including type 1 diabetes (T1D). However, allelic and copy number variation in the KIR region effectively mask it from standard genome-wide association studies: single nucleotide polymorphism (SNP) probes targeting the region are often discarded by standard genotype callers since they exhibit variable cluster numbers. Quantitative Polymerase Chain Reaction (qPCR) assays address this issue. However, their cost is prohibitive at the sample sizes required for detecting effects typically observed in complex genetic diseases. We propose a more powerful and cost-effective alternative, which combines signals from SNPs with more than three clusters found in existing datasets, with qPCR on a subset of samples. First, we showed that noise and batch effects in multiplexed qPCR assays are addressed through normalisation and simultaneous copy number calling of multiple genes. Then, we used supervised classification to impute copy numbers of specific KIR genes from SNP signals. We applied this method to assess copy number variation in two KIR genes, \textit{KIR3DL1} and KIR3DS1, which are suitable candidates for T1D susceptibility since they encode the only KIR molecules known to bind with HLA-Bw4 epitopes. We find no association between KIR3DL1/3DS1 copy number and T1D in 6744 cases and 5362 controls; a sample size twenty-fold larger than in any previous KIR association study. Due to our sample size, we can exclude odds ratios larger than 1.1 for the common KIR3DL1/3DS1 copy number groups at the 5% significance level. We found no evidence of association of KIR3DL1/3DS1 copy number with T1D, either overall or dependent on HLA-Bw4 epitope. Five other KIR genes, KIR2DS4, KIR2DL3, KIR2DL5, KIR2DS5 and KIR2DS1, in high linkage disequilibrium with KIR3DL1 and KIR3DS1, are also unlikely to be significantly associated. Our approach could potentially be applied to other KIR genes to allow cost effective assaying of gene copy number in large samples.
    BMC Genomics 04/2014; 15(1):274. DOI:10.1186/1471-2164-15-274 · 3.99 Impact Factor
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