Genetics and epigenetics of rheumatoid arthritis

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Abstract
A rational approach to the management of rheumatoid arthritis (RA) begins with understanding the disease, development of which can be influenced by environmental, genetic and epigenetic factors. Genetic and epigenetic data in RA are revealing insights into pathogenesis and revitalizing the shared epitope hypothesis. These advances are discussed in this Review, alongside approaches to integrating the findings of genetic and functional studies. Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions.

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