A broad range of common diseases, such as inflammatory bowel disease, rheumatoid arthritis and cancer, are associated with variants in the genome sequence that regulate the expression of genes involved in the immune system. In the course of investigating how these variants affect a person’s susceptibility to disease, a team of researchers at the Wellcome Trust Centre for Human Genetics has found that stimulating cells involved in fighting infection often provokes genes of interest to reveal themselves.
Many genes that are effectively dormant in resting cells spring into action when stimulated by signals associated with bacterial or viral infection, often activating networks of other genes in the process. Benjamin Fairfax and other members of Dr Julian Knight's group, working with colleagues at WTCHG and the Wellcome Trust Sanger Institute in Cambridge, have tracked the way that genetic variation between individuals affects these induced networks of gene expression across the human genome.
The team collected monocytes, cells that circulate in the bloodstream and provide the first line of defence against disease, from over 400 healthy human volunteers in Oxfordshire. After challenging these cells with signals that provoke an inflammatory response, they collected data on genes that were expressed in the cells across the whole genome, and compared it with expression data from the same cells in a resting state.
The study, published in the journal Science, revealed that the induced expression of particular genes depended on one’s genetic make-up, with some individuals responding more vigorously than others and for some genes, in opposite directions. They confirmed that many genetic variants affected gene expression only once cells had been stimulated by an inflammatory signal, leading to the discovery of many new variants not previously associated with gene expression. Notably, some of these variants had been shown in previous studies to increase susceptibility to many different diseases.
The study also showed that in some cases the effects of such genetic variants could be detected not only at the genes to which they were closest, but also at genes on different chromosomes. In one instance stimulation revealed the effects of a single variant on expression of a network of 19 active genes, which mapped onto the known signalling cascade triggered by the molecule interferon-β.
Dr Knight says that the next step is to study such networks in people who are suffering from disease. ‘If we want to understand the functional consequences of the genetic differences between people,’ he says, ‘we need to look at the right cells, and under conditions that are relevant to disease.’
Agents that block the early mediators of such networks could provide new insights into the biology of the immune response and shed light on disease processes. This in turn could lead to new therapeutic strategies. ‘You might find that a network that is active in Crohn’s disease, for example, overlaps with that for rheumatoid arthritis’, says Knight. ‘If so, we might be able to use existing drugs for new purposes.’
Benjamin P. Fairfax, Peter Humburg, Seiko Makino, Viven Naranbhai, Daniel Wong, Evelyn Lau, Luke Jostins, Katherine Plant, Robert Andrews, Chris McGee, Julian C Knight, Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression, Science. 2014: 343, 7 March 2014.