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Identifying the immune interactions underlying HLA class I disease associations.

ABSTRACT: Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8+ T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8+ T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease.

SUBMITTER: Debebe BJ

PROVIDER: S-EPMC7253178 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Identifying the immune interactions underlying HLA class I disease associations.

Debebe Bisrat J BJ Boelen Lies L Lee James C JC Thio Chloe L CL Astemborski Jacquie J Kirk Gregory G Khakoo Salim I SI Donfield Sharyne M SM Goedert James J JJ Asquith Becca B

eLife 20200402

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8<sup>+</sup> T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound ...[more]

PMID: 32238263

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Project description:Until recently, human leucocyte antigen (HLA) class II-independent associations with type 1 diabetes (T1D) in the Major Histocompatibility Complex (MHC) region were not adequately characterized owing to insufficient map coverage, inadequate statistical approaches and strong linkage disequilibrium spanning the entire MHC. Here we test for HLA class II-independent associations in the MHC using fine mapping data generated by the Type 1 Diabetes Genetics Consortium (T1DGC).We have applied recursive partitioning to the modelling of the class II loci and used stepwise conditional logistic regression to test approximately 1534 loci between 29 and 34 Mb on chromosome 6p21, typed in 2240 affected sibpair (ASP) families.Preliminary analyses confirm that HLA-B (at 31.4 Mb), HLA-A (at 30.0 Mb) are associated with T1D independently of the class II genes HLA-DRB1 and HLA-DQB1 (P = 6.0 x 10(-17) and 8.8 x 10(-13), respectively). In addition, a second class II region of association containing the single-nucleotide polymorphism (SNP), rs439121, and the class II locus HLA-DPB1, was identified as a T1D susceptibility effect which is independent of HLA-DRB1, HLA-DQB1 and HLA-B (P = 9.2 x 10(-8)). A younger age-at-diagnosis of T1D was found for HLA-B*39 (P = 7.6 x 10(-6)), and HLA-B*38 was protective for T1D.These analyses in the T1DGC families replicate our results obtained previously in approximately 2000 cases and controls and 850 families. Taking both studies together, there is evidence for four T1D-associated regions at 30.0 Mb (HLA-A), 31.4 Mb (HLA-B), 32.5 Mb (rs9268831/HLA-DRA) and 33.2 Mb (rs439121/HLA-DPB1) that are independent of HLA-DRB1/HLA-DQB1. Neither study found evidence of independent associations at HLA-C, HLA-DQA1 loci nor in the UBD/MAS1L or ITPR3 gene regions. These studies show that to find true class II-independent effects, large, well-powered sample collections are required and be genotyped with a dense map of markers. In addition, a robust statistical methodology that fully models the class II effects is necessary. Recursive partitioning is a useful tool for modelling these multiallelic systems.

Dataset Information

Identifying the immune interactions underlying HLA class I disease associations.

Publications

Identifying the immune interactions underlying HLA class I disease associations.

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