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Ethnogenetic heterogeneity of rheumatoid arthritis—implications for pathogenesis

Nature Reviews Rheumatology volume 6, pages 290–295 (2010)Cite this article

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Abstract

Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are generally considered multifactorial—that is, they involve both genetic and environmental factors. Technical advances in human genetics over the past 5 years have enabled the survey of the entire human genome for disease susceptibility genes and have contributed to a greater understanding of the molecular mechanisms underlying autoimmunity. Among the genetic predisposition factors identified to date, some variants have been found to be restricted to specific ethnic groups, which might reflect migration history and the natural selection that shaped genetic variation in these populations. Other genetic factors could also have exerted different magnitudes of risk for the disease among the different populations, which might be explained by their interactions with other genetic and environmental factors. These pieces of evidence suggest that substantial heterogeneity exists in the genetics underlying autoimmunity among different ethnic populations. This Review discusses the genetic heterogeneity in autoimmunity, with a focus on rheumatoid arthritis, between Asian and European populations. In addition to the most-studied and well-characterized gene HLA-DRB1, we will also describe examples of the gene–environment interactions between PADI4 and smoking, and the gene–gene interactions between PTPN22 and FCRL3.

Key Points

  • Genome-wide association studies have revealed multiple genetic risk factors for rheumatoid arthritis (RA) in addition to the well-studied HLA-DRB1 locus

  • Some of the RA-associated genetic factors are restricted to specific ethnic populations, indicating the presence of genetic heterogeneity in RA

  • The genetic heterogeneity might be primarily explained by the exclusive presence of a disease susceptibility allele in a particular population (for example, PTPN22 variant in European populations and HLA-DRB1*0901 in Asian populations)

  • Gene–environment interactions and gene–gene interactions might affect the contribution of each genetic factor to disease susceptibility, and account for the genetic heterogeneity between the populations

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Figure 1: Genetic differences observed in PADI4 between Asian and European populations.
Figure 2: Upmodulation of the antigen receptor affinity threshold by PTPN22 and FCRL3.

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Acknowledgements

The authors thank members of the Laboratory for Autoimmune Diseases, RIKEN, Tokyo for their assistance. This work was supported by grants from the Center for Genomic Medicine, RIKEN; the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Leading Project); and the Ministry of Health, Labor, and Welfare of Japan (Research on Intractable Diseases).

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Authors and Affiliations

  1. Laboratory for Autoimmune Diseases, Center for Genomic Medicine, RIKEN, 113-0033, Tokyo, Japan

    Yuta Kochi & Akari Suzuki

  2. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, 606-8501, Kyoto, Japan

    Ryo Yamada

  3. Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 113-0033, Tokyo, Japan

    Kazuhiko Yamamoto

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Correspondence to Kazuhiko Yamamoto.

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Kochi, Y., Suzuki, A., Yamada, R. et al. Ethnogenetic heterogeneity of rheumatoid arthritis—implications for pathogenesis. Nat Rev Rheumatol 6, 290–295 (2010). https://doi.org/10.1038/nrrheum.2010.23

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