Genetics and Epigenetics of Autoimmune Diseases


Elucidating the interrelationships between genetic and epigenetic factors represents an important challenge in our knowledge of autoimmune diseases (AID). Accordingly, the first clues support (1) the initiating role of environmental factors (e.g. infectious agents, drugs, diet and UV light exposure) on the epigenetic machinery, (2) the presence of specific cell‐type epigenetic marks in AID (DNA methylation/demethylation, histone modifications and chromatin organisation), (3) the critical role of epigenetic processes in the control of transposons and key immune protein‐coding gene expression, (4) the presence of AID‐associated genetic risk variants that are predominantly present within cell‐type‐specific and epigenetically controlled long‐range gene‐regulatory sequences and, last but not the least, (5) the detection of AID‐specific transcriptome hallmarks that are in part related to microRNA dysregulation. Altogether, advances in our understanding of the mechanisms involved in the development of AID offer novel ways for the diagnosis, prognosis and therapy of AID patients.

Key Concepts

  • Autoimmune diseases (AID) are complex diseases.
  • Genetics, epigenetics and environmental factors control AID.
  • AID genetic risk variants are mainly located in the epigenetic AID‐related hotspots.
  • Epigenetic modifications are cell specific in AID.
  • Environmental factors control cell‐specific epigenetic modifications in AID.

Keywords: genetics; epigenetics; DNA methylation; DNA demethylation; histone modifications; microRNAs; autoimmune diseases

Figure 1. The list of genetic variants detected in patients with systemic lupus erythematosus (SLE) is growing with the development of the molecular biology technologies to characterise variants within coding regions (1980–2000), variants throughout the human genome (from 2005) and now copy number variations (CNV), short tandem repeats (STR) and variable number of tandem repeats (VNTR). In parallel, a decrease was observed in the activity of DNMTs with overexpression of DNA methylation sensitive genes such as human endogenous retroviruses (HERV) in lymphocytes (T cells and later B cells) from SLE patients. The inhibition can be reproduced in mice with DNA demethylating drugs (procainamide and hydralazine), which are well‐known to induce lupus in humans.
Figure 2. Genetic analysis of autoimmune diseases (AID) reveals more than 100 causal genetic variations ( In this figure, we have positioned 71 human disease loci (horizontal bar) from four AID: systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), rheumatoid arthritis (RA) and type 1 diabetes (T1D). The related gene is indicated when known, and gene‐coding mutations (missense) are also indicated (*).
Figure 3. The fine mapping of causal variants in autoimmune diseases reveals that they map predominantly enhancer‐like elements (60%). These long‐range regulatory elements are cell‐type specific and hot spots for epigenetic factors. The other risk factors are related to mutations within the promoter, the coding region (silent, missense and nonsense mutations), introns (splicing mutations) and 3′ UTR (miRNA target).


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Further Reading

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Konsta, Orsia D, Le Dantec, Christelle, Brooks, Wesley H, and Renaudineau, Yves(May 2015) Genetics and Epigenetics of Autoimmune Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023593]