RESEARCH HIGHLIGHTS

NPG

IMMUNOGENETICS Tracking immune activity across the

Genome-wide association studies lipopolysaccharide (LPS) or to the pro- expression in cells stimulated with (GWASs) have been successful in inflammatory cytokine interferon-γ LPS, IFNβ or influenza . The linking genetic variants with certain (IFNγ). They found that a diverse authors demonstrated how CRISPR immune diseases, but the precise set of immune-related genes showed (clustered regularly interspaced short functional consequences of these changes in their expression levels palindromic repeats) technology can variants are poorly understood. Now, after stimulation, including genes that be used to modify the genome and two studies published in Science have encode transcription factors, cytokines validate an association between a mapped how human genetic varia- and cytokine receptors. Furthermore, genetic variant and gene expression. tion influences gene expression in the authors found that some genetic Similarly to Fairfax et al., they iden­ resting and activated innate immune variants — such as one that is located tified hundreds of loci containing cell subsets. near IFNB1 (which encodes IFNβ) genetic variants that are associated GWASs have identified genetic — were associated with early changes with gene expression in a context- variants that are associated with com- in gene expression following LPS specific manner in DCs. For example, mon diseases, such as inflammatory stimulation (after 2 hours), but they the authors identified a variant that bowel disease and rheumatoid arth­ could also detect different downstream affects the expression of IRF7 (which ritis, and most of these variants are effects of these same variants on gene encodes interferon regulatory factor 7, found in non-coding regions that are expression at later stages (24 hours a protein that mediates antiviral proposed to regulate the expression after LPS stimulation). responses) as well as the targets of of immune genes. The two studies The authors compared their this transcription factor. Such genetic compared gene expression across expression data with disease loci in the variants may contribute to the diverse the whole genome in monocytes GWAS variant catalogue and found immune responses to influenza virus and dendritic cells (DCs) that were that 467 of the genetic variants that infection that are seen in humans. exposed to inflammatory stimuli with affected gene expression in monocytes Based on the approach taken by that in unstimulated cells. Whereas were located in disease-associated these two studies, further investiga- a subset of genetic variants affected gene regions. Specifically, these tion of other immune cell types, gene expression levels in unstimu- were regions that had previously and also of samples from patients lated cells, many variants only been associated with inflammatory, with immune-related diseases, will the functional affected gene expression in those that autoimmune and gastroenterological improve our understanding of how had been stimulated by an inflamma- diseases, whereas variants associated human affects the effects of tory signal. Thus, many variants that with cancer, reproductive conditions immune response. In addition, such some disease- had not previously been associated or cardiovascular disease were work will provide an insight into the associated with changes in gene expression were under-represented. Interestingly, mechanisms underpinning the asso- genetic identified. Furthermore, these stud- 248 variants only affected gene ciation of particular genetic variants ies showed that genetic variants can expression in stimulated cells, with disease. variants influence the expression of genes that suggest­ing that the functional effects Elisabeth Kugelberg may only be are in close proximity and also those of some disease-associated genetic ORIGINAL RESEARCH PAPERS Fairfax, B. P. et al. detectable that are on different . variants may only be detectable in a Innate immune activity conditions the effect of Fairfax et al. collected human context-specific manner. regulatory variants upon monocyte gene in a context- + expression. Science http://dx.doi.org/10.1126/ CD14 monocytes from 432 healthy The study by Lee et al. used DCs science.1246949 (2014) | Lee, M. N. et al. Common specific Europeans and investigated changes from >500 healthy individuals from genetic variants modulate pathogen-sensing manner in gene expression in these cells different ethnic backgrounds to map responses in human dendritic cells. Science http://dx.doi.org/10.1126/science.1246980 (2014) before and after exposure to bacterial genetic variants that influence gene

NATURE REVIEWS | VOLUME 14 | APRIL 2014

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