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GENETIC VARIATION

An evolving hypothesis in autoimmune disease genetics

Nature Reviews Genetics volume 23, pages 458–459 (2022)Cite this article

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Genetic variations in the major histocompatibility complex (MHC) region at chromosomes 6p21 are strongly associated with the risk of autoimmune diseases such as rheumatoid arthritis (RA), a common autoimmune disease characterized by inflammation and destruction of the joints. The MHC region includes multiple human leukocyte antigen (HLA) genes, which encode molecules that regulate adaptive immune responses and self-recognition by presenting antigens. Fine-mapping disease-causal HLA variants has been challenging given their highly polymorphic features, including many alleles and amino acid polymorphisms, as well as their complex linkage disequilibrium structure.

The MHC region accounts for around one-third of the overall genetic component of RA. Candidate gene-based approaches reported that several HLA-DRB1 variants, such as the common HLA-DRB1*04 allele, conferred strong RA risk. However, why any single HLA-DRB1 allele cannot parsimoniously explain overall RA risk was unclear. In 1987, Gregersen et al. proposed the ‘shared epitope’ hypothesis to answer this question.

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References

Original article

  • Gregersen, P. K. et al. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis. Rheum. 30, 1205–1213 (1987)

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Related article

  • Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012)

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Authors and Affiliations

  1. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Yukinori Okada

  2. Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

    Yukinori Okada

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  1. Yukinori Okada
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Correspondence to Yukinori Okada.

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The author declares no competing interests.

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Cite this article

Okada, Y. An evolving hypothesis in autoimmune disease genetics. Nat Rev Genet 23, 458–459 (2022). https://doi.org/10.1038/s41576-022-00482-9

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