Genetics of Vitiligo

Abstract

Vitiligo is an autoimmune disease that results in destruction of skin melanocytes and patches of white skin and hair. Family studies of vitiligo demonstrated that a strong, but complex genetic component underlies disease risk and that vitiligo often occurs with other autoimmune diseases, suggesting shared autoimmune susceptibility. Genome‐wide linkage and association studies have identified over 50 vitiligo susceptibility loci, with most loci harbouring genes involved in immune regulation, apoptosis or melanocyte function. The identified loci fit together in a model of melanocyte‐directed autoimmunity, and many loci are shared with other autoimmune diseases. Surprisingly, some genetic vitiligo susceptibility alleles are inversely associated with melanoma, suggesting that vitiligo represents enhanced immune surveillance against melanoma. Genetic studies of vitiligo have greatly advanced understanding of vitiligo pathobiology and may additionally provide insights into melanoma and other autoimmune disease.

Key Concepts

  • Vitiligo is a multifactorial disease, in which multiple genetic and environmental factors contribute to disease risk.
  • The genetic architecture of vitiligo is typically (and perhaps always) polygenic, with a strong genetic component underlying disease risk.
  • Over 50 genetic loci have been associated with vitiligo risk; these loci fit together in a model of melanocyte‐directed autoimmune pathobiology.
  • Most variants associated with vitiligo are in noncoding regions and presumably affect gene regulation. Nevertheless, some associated coding variants and physical interaction among proteins encoded by some vitiligo susceptibility genes provide special insights into pathogenesis.
  • Vitiligo shares many genetic risk factors with other autoimmune diseases with which it is epidemiologically associated, supporting a component of common autoimmune pathogenesis.

Keywords: vitiligo; autoimmunity; linkage analysis; genome‐wide association study; genetic studies

Figure 1. A woman with generalised vitiligo. Source: Spritz, https://genomemedicine.biomedcentral.com/articles/10.1186/gm199. Licensed under CC by 4.0.
Figure 2. Shared genetic associations of vitiligo with other autoimmune diseases. Black circles indicate a genetic association in the same region in vitiligo and with the other autoimmune disease. Only associations identified by GWAS and meeting the genome‐wide significance criterion (P < 5 × 10−8) are shown. RA, rheumatoid arthritis; T1D, type 1 diabetes mellitus; IBD, inflammatory bowel disease; AITD, autoimmune thyroid disease; MS, multiple sclerosis; SLE, systemic lupus erythematosus; MG, myasthenia gravis.
Figure 3. General framework of vitiligo pathogenesis. Autoreactive T‐lymphocytes escape negative selection (in this example, autoreactive T‐lymphocytes recognise melanocytic peptide antigen derived from OCA2). At the site of skin damage, DAMPs are released, activating a skin dendritic cell, which then phagocytoses debris from damaged melanocytes, resulting in presentation of peptide antigen from OCA2 on its cell surface. The autoreactive T helper lymphocyte recognises the OCA2 peptide presented on the cell surface the dendritic cell and releases cytokines that activate an OCA2‐autoreactive cytotoxic T‐lymphocyte, resulting in cytolysis of a healthy melanocyte presenting the OCA2 peptide antigen. Reproduced with permission from Spritz and Andersen . © Elsevier.
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Further Reading

Birlea SA, Spritz RA and Norris DA (2012) Vitiligo. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ and Wolff K (eds) Fitzpatrick's Dermatology in General Medicine, 8th edn, pp. 792–803. New York: McGraw‐Hill.

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Richmond JM, Frisoli ML and Harris JE (2013) Innate immune mechanisms in vitiligo: danger from within. Current Opinion in Immunology 25: 676–682.

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Roberts, Genevieve HL, and Spritz, Richard A(Dec 2018) Genetics of Vitiligo. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026934]