Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46) and healthy controls (n = 43), revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases. Author Summary The human immune system has evolved to protect us from infection and cancer, whilst avoiding damage to healthy tissue. If this complex system goes wrong, immune cells may cause inappropriate inflammation and damage, resulting in clinical disease. Examples include inflammatory bowel disease and autoimmune vasculitis, characterised by inflammation in the gut and blood vessels respectively. Genetic studies have identified many variants in our DNA code that predispose to such immune-mediated diseases. The majority of these variants lie outside protein-coding regions, and so how they influence disease risk remains largely unclear. Examining how genetic variants affect gene expression can help bridge this gap in our knowledge, but these effects are highly dependent on the cellular or environmental context such as tissue type or cellular activation status. We investigated the genetic control of gene expression in five white blood cell subtypes taken from patients with active inflammatory bowel disease and autoimmune vasculitis, and from healthy controls. We report the novel observation of distinct variants that only affect gene expression in patients with active inflammatory disease, and show that these effects can disappear following treatment. These findings provide new insights into the genetic basis of important immune-mediated diseases.
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