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Systemic autoimmune/inflammatory conditions are complex both at the clinical and pathomechanistic level. While a number of rare conditions are caused by mutations in single genes, most autoimmune/inflammatory diseases are underlined by multiple genetic variants which, through poorly characterised or unknown processes, confer so-called ‘genetic susceptibility’. The influence of environmental factors necessary for the expression of a clinical entity is usually mandated in the form of epigenetic changes.1–3
Over the last decade, genome-wide association studies (GWAS) have identified a wealth of associations between genetic variants and autoimmune/inflammatory conditions. Studies have provided compelling evidence for germline polymorphisms and/or copy-number variants contributing to the risk for the development of disease. In most cases, genetic variants only increased the risk of developing disease, while the underlying disease-causing mechanisms remained unclear. Furthermore, healthy individuals may also carry risk alleles for inflammatory conditions while never developing symptoms.4 Understanding the contribution of genetic variants to disease expression is complex because most disease-associated gene variants are located in intergenic or intronic (non-coding) regions, limiting our understanding of their exact impact on genes, their influence on gene expression and underlying molecular events. The fact that a significant proportion of disease-associated polymorphisms are located distant from genes, perhaps not even affecting neighbouring gene expression, led to the hypothesis that genetic variants may interfere with the regulation of distant genes on the same or even other chromosomes.
Indeed, interactions between genes and/or regulatory regions through DNA folding (allowing for physical contact between otherwise distant regions) and/or interactions between chromosomes mediating regulatory events has been suggested. Several genes linked to the immune response are regulated by long-distance chromatin interactions, including (but not limited to) cytokine genes in the Th2 cluster (IL4, IL5 and IL13 on chromosome …
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