Epistasis and immunity: the role of genetic interactions in autoimmune diseases

Abstract

Autoimmune disorders are a complex and varied group of diseases that are caused by breakdown of self-tolerance. The aetiology of autoimmunity is multi-factorial, with both environmental triggers and genetically determined risk factors. In recent years, it has been increasingly recognized that genetic risk factors do not act in isolation, but rather the combination of individual additive effects, gene-gene interactions and gene-environment interactions determine overall risk of autoimmunity. The importance of gene-gene interactions, or epistasis, has been recently brought into focus, with research demonstrating that many autoimmune diseases, including rheumatic arthritis, autoimmune glomerulonephritis, systemic lupus erythematosus and multiple sclerosis, are influenced by epistatic interactions. This review sets out to examine the basic mechanisms of epistasis, how epistasis influences the immune system and the role of epistasis in two major autoimmune conditions, systemic lupus erythematosus and multiple sclerosis.

Figure 1

Approaches to research: one of the ‘pinnacles’ of medical research is the identification of novel therapeutic targets. In polygenic diseases, the most basic level (‘the foundation’) is genetic studies, which should include analysis of epistatic interactions. Genetic studies support transcriptional analysis, which provides a more comprehensive view of the gene within the cellular system. Finally, the top level of research is functional studies, which can lead to the discovery of novel therapeutic targets.