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Genetics and epigenetics of rheumatoid arthritis

Abstract

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.

Key Points

  • Nearly 60 loci associated with susceptibility to rheumatoid arthritis (RA) have been identified across multiple populations, and are at least partially shared between ethnicities

  • Five amino acid positions, all located in peptide-binding grooves, almost completely explain the association between MHC polymorphisms and RA risk, revitalizing the 'arthritogenic peptide hypothesis'

  • Cumulatively, genetic markers identified to date explain only 50% of RA heritability

  • Using genetics to identify causative disease pathways represents a major challenge for the future

  • Epigenetic changes in RA remain underexplored and represent a promising new area to link genetics and gene expression with disease risk

  • Although genetics can be used to stratify disease risk, clinical predictions for the development and progression of RA cannot yet be performed with sufficient accuracy in individual patients

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Figure 1: Antigen-binding groove HLA amino acid substitutions and influence on susceptibility to RA.
Figure 2: RA genetic susceptibility loci identified to date, and cumulative proportion of observed variance in disease susceptibility explained thus far.
Figure 3: Mapping of 11 RA susceptibility loci to pathways involved in the 'T-cell–dendritic-cell dialogue'.
Figure 4: Network analysis to infer functional characteristics of genetic variants implicated in RA susceptibility.

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Acknowledgements

S. Viatte's research activities are supported by a grant from the Swiss Foundation for Medical-Biological Scholarships (SSMBS), managed by the Swiss National Science Foundation and financed by a donation from Novartis (PASMP3_134380). The work of S. Raychaudhuri is supported by grants from the National Institutes of Health (5K08AR055688 and 1R01AR062886) and an Arthritis Foundation Innovator Award. This manuscript was also funded by a core programme grant from Arthritis Research UK (17552).

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Viatte, S., Plant, D. & Raychaudhuri, S. Genetics and epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9, 141–153 (2013). https://doi.org/10.1038/nrrheum.2012.237

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