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REGVARMHC Report Summary

Project ID: 281824
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - REGVARMHC (Genetic and epigenetic determinants of allele-specific gene expression in the human Major Histocompatibility Complex)

This project aimed to determine the functional consequences of genetic variation associated with risk of developing autoimmune, infectious and inflammatory disease. The work focused on genetic variation involving the human Major Histocompatibility Complex (MHC) on chromosome 6. This is a highly polymorphic region of the human genome that shows striking disease associations but the specific genetic variants and genes responsible for these associations remain unresolved. We hypothesised that the functional basis for disease associations may involve effects of genetic variation on the expression of genes within the MHC and genome-wide. Such work is important as it can inform understanding of disease mechanisms and opportunities for therapeutic intervention.

In order to identify functionally important regulatory genetic variants that modulate gene expression we adopted a number of approaches. Firstly, we sought to understand better the haplotypic structure of genetic variation in the MHC and how we could use next generation sequencing technologies to accurately quantify gene expression for genes in this region. Secondly, we aimed to investigate gene expression in disease relevant contexts, namely primary immune cell types in different activation states, and complemented this by detailed characterisation of epigenetic regulation. Thirdly, we mapped differences in gene expression as a quantitative trait enabling association of specific genetic variants with expression of particular genes. We did this for a range of immune cell types and activation states in healthy volunteers. Fourthly, we characterised specific genes and regulatory elements in the MHC to understand mechanism.

The study was conducted over 5 years at the University of Oxford. We made advances in understanding the nature of genetic variation in the MHC, how it may modulate gene expression and the consequences of this for disease. More broadly, we demonstrated the importance of context-specificity in the action of regulatory genetic variants and produced route maps of putative functional variants and their modulated genes for different immune cell types and activation states relevant to innate immunity. We generated substantive novel datasets that have been made available to the scientific community to progress work in this area, notably for the interpretation of genome-wide association studies. We discovered new functional variants, for example involving the MHC master regulator CIITA and the gene ZFP57 involved in imprinting. We also developed new bioinformatics tools for analysing functional genomic data that are open access. During this grant, we had the opportunity to apply the approaches in the context of sepsis where the role of MHC was investigated and regulatory variants associated with a poor outcome group were identified. Going forward, the work will be relevant to a number of different immune-mediated disease states including a range of autoimmune and infectious diseases. Further work will also be needed to establish causal mechanisms through for example new genome editing approaches.

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United Kingdom
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