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  • Review Article
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Update on the genetic architecture of rheumatoid arthritis

Nature Reviews Rheumatology volume 13, pages 13–24 (2017)Cite this article

Subjects

Key Points

  • The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported

  • Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA development; log-additive and non-log-additive effects of HLA alleles explain HLA–RA associations

  • The majority of non-HLA associations are mapped at noncoding variants that colocalize with cell-type-specific characteristics (for example, histone markers or enhancers) in CD4+ T cells

  • Pinpointing a single causal gene in a locus that contains multiple genes usually requires additional 'omics' data

  • RA-risk loci generally contain genes related to T-cell and B-cell pathways, cytokine signalling pathways, proliferation and/or impaired haematopoietic and immune systems

  • Many proteins encoded within RA-risk loci, and their interaction partners, are the targets of currently approved therapies, implicating a potential guiding role for human RA genetics data in drug discovery and repurposing

Abstract

Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.

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Figure 1: Location of HLA variants known to be associated with anti-citrullinated protein autoantibody-positive rheumatoid arthritis risk.
Figure 2: Interaction effects between heterozygous HLA-DRB1 alleles on anti-citrullinated protein autoantibody-positive rheumatoid arthritis risk.
Figure 3: Example of how a noncoding regulatory rheumatoid arthritis-associated single nucleotide polymorphism might result in a rheumatoid arthritis phenotype.
Figure 4: Simplified T cell and antigen presenting cell pathways involving rheumatoid arthritis-risk loci gene products.
Figure 5: Simplified T-cell differentiation pathways involving rheumatoid arthritis-risk loci gene products.

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Acknowledgements

K.K. and S.C.B. are funded by the Korea Healthcare Technology R&D Project from the Ministry for Health and Welfare, Republic of Korea, grant numbers HI15C3182 (K.K) and HI13C2124 (S.C.B.).

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  1. Department of Biology, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, 02447, Seoul, Republic of Korea

    Kwangwoo Kim

  2. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 222–1 Wangsimni-ro, Seongdong-gu, 04763, Seoul, Republic of Korea

    So-Young Bang, Hye-Soon Lee & Sang-Cheol Bae

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K.K. and S.C.B. collected data for the article and wrote the manuscript. All authors provided substantial contributions to the discussion of content and reviewed and edited the manuscript before submission.

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Kim, K., Bang, SY., Lee, HS. et al. Update on the genetic architecture of rheumatoid arthritis. Nat Rev Rheumatol 13, 13–24 (2017). https://doi.org/10.1038/nrrheum.2016.176

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