Download Genetics of gene expression in immunity and infection

Genetics of gene expression in immunity and infection
Julian Knight, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive
Oxford OX3 7BN UK
Genome-wide association studies have highlighted the role of genetic associations with susceptibility
to common inflammatory diseases, highlighting potential new insights into disease pathogenesis and
opportunities for therapy. However understanding the functional basis of these associations and
delivering translational utility remains a significant challenge to the field. Non-coding regulatory
genetic variants are most commonly implicated in such studies. Recent work highlights how such
variants are also major drivers of diversity in the immune response transcriptome. This talk will
discuss approaches we are taking to try and establish functional links between immune phenotypeassociated regulatory genomic and epigenomic variation, and specific modulated genes and
pathways. I will describe insights from the application of expression quantitative trait (eQTL) mapping
to define genomic modulators of the global transcriptomic response in different primary immune cell
populations and to specific innate immune stimuli in health and disease. This work highlights the
extent of local and distant context-specific eQTL, enabling resolution of immunoregulatory variants
and the identification of specific modulated genes involving disease associated loci. Examples will be
described showing how mapping trans-regulatory loci can be a powerful approach for discovery and
dissection of gene networks informative for disease. I will also show how we have applied analysis of
the genetics of gene expression in patients with sepsis admitted to intensive care, revealing new
insights into disease pathogenesis. Further progress in this area will require characterisation of
associated variants in the context-specific disease relevant epigenomic landscape in which they may
act, requiring careful consideration of relevant immune cell types and environmental modulators to
study, together with evidence establishing mechanism, for example based on mapping chromatin
interactions and application of genome editing techniques.