Genetic Susceptibility to Autoimmune Disorders


Susceptibility to autoimmune disorders results from the interaction of multiple genetic variations that regulate the threshold of autoreactivity. Alleles of susceptibility to autoimmune diseases are frequent in the general population, when considered individually. However, if several of them (probably a few dozens) are combined in a single individual, a putative threshold is reached, beyond which gene interactions lead to pathological manifestations.

Genome‐wide association studies (GWAS) have identified numerous genetic variations, in particular single nucleotide polymorphisms (SNPs), to be significantly enriched in patients with autoimmune disorders. Strikingly, many of them (e.g. in the PTPN22, STAT4, IRF5 and MHC genes) are associated with several conditions, thereby indicating that common mechanisms can lead to loss of tolerance for self‐antigens.

The identification of new genes of susceptibility to autoimmune disorders has opened large avenues of research about their role in (thus far unknown) pathogenic pathways and the possibility to modulate their contribution into the generation or amplification of autoimmune mechanisms.

Key Concepts:

  • Genetic susceptibility to autoimmune disorders is polygenic.

  • Genetic studies in autoimmunity can be biased by numerous confounding factors.

  • Genes of susceptibility can be categorised in three theoretical functional pathways: loss of tolerance for self‐antigens, amplification of the autoimmune response and target‐organ sensitivity.

Keywords: genetic susceptibility; genome‐wide association studies; single nucleotide polymorphism; autoimmunity; systemic lupus erythematosus; rheumatoid arthritis; MHC genes; non‐MHC genes

Figure 1.

Threshold susceptibility theory.



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Further Reading

Kanta H and Mohan C (2009) Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end‐organ inflammation. Genes and Immunity 10: 390–396.

Pascual V, Allantaz F, Patel P et al. (2008) How the study of children with rheumatic diseases identified interferon‐alpha and interleukin‐1 as novel therapeutic targets. Immunology Reviews 223: 39–59.

Rhodes B and Vyse TJ (2008) The genetics of SLE: an update in the light of genome‐wide association studies. Rheumatology (Oxford) 47: 1603–1611.

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How to Cite close
Lauwerys, Bernard R(Jun 2010) Genetic Susceptibility to Autoimmune Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022406]