Review Article | Published:

Genetics and epigenetics of rheumatoid arthritis

Nature Reviews Rheumatology volume 9, pages 141153 (2013) | Download Citation

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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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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  1. Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK

    • Sebastien Viatte
  2. NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK

    • Darren Plant
  3. Divisions of Rheumatology and Genetics, New Research Building (NRB), 77 Avenue Louis Pasteur, Suites 250/255, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA

    • Soumya Raychaudhuri

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All authors contributed equally to researching data for the article, writing the article, discussions of the content, and review and/or editing of the article before submission.

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Correspondence to Soumya Raychaudhuri.

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https://doi.org/10.1038/nrrheum.2012.237

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