Genetics of Vitiligo

Abstract

Vitiligo reflects simultaneous contributions of multiple genetic risk factors and environmental triggers. Genomewide association studies have discovered approximately 50 genetic loci contributing to vitiligo risk. At many vitiligo susceptibility loci, the relevant genes and DNA sequence variants are identified. Many encode proteins involved in immune regulation, several play roles in cellular apoptosis, and others regulate functions of melanocytes. Although many of the specific biologic mechanisms need elucidation, it is clear that vitiligo is an autoimmune disease involving a complex relationship between immune system programming and function, aspects of the melanocyte autoimmune target, and dysregulation of the immune response.

Keywords: Autoimmunity; Gene; Genetic epidemiology; Genetic linkage; Genomewide association study; Vitiligo.

Figure 1

General framework of vitiligo pathogenesis. During early development, a T lymphocyte repertoire is selected by positive selection of immunocompetent immature T lymphocytes in the thymic cortex. Immunocompetent T lymphocytes that recognize “self” antigens expressed by medullary epithelial cells undergo negative selection and undergo apoptosis. Immunocompetent immature T lymphocytes that do not encounter a cognate “self” antigen then exit the thymus to the peripheral circulation. In the skin, many or most cases of vitiligo initiate with skin damage, often UV exposure or trauma, a process termed “Koebnerization.” Damaged melanocytes apoptose and release molecules that act as “damage-associated molecular patterns” (DAMPs), which stimulate activation of local dendritic cells. Dendritic cells engulf melanosomal proteins, which are degraded in the proteasome, and fragments that act as peptide antigens are presented by HLA class II molecules on the dendritic cell surface. Immature T lymphocytes that express cognate T cell receptors bind these “self” antigens and are activated to express co-stimulatory molecules that result in cell proliferation and differentiation into CD8+ effector cytotoxic T lymphocytes, with the assistance of CD4+ T helper cells. The resultant activated cytotoxic T lymphocytes recognize and bind the cognate “self” antigen presented by HLA class I molecules on the melanocyte surface, assisted by interaction of FAS ligand on the T cell and FAS on the target melanocyte. The cytotoxic T lymphocyte then elaborates granzyme B and perforin, which induce apoptosis of the target melanocyte. Almost all of these processes involve proteins that are encoded by one or more genes associated with genetic susceptibility to vitiligo.

Figure 2

Shared genetic associations of vitiligo with other autoimmune diseases and with pigmentation and melanoma phenotypes. Blue circles indicate shared genetic associations between vitiligo and other autoimmune diseases. Red circles indicate shared genetic associations between vitiligo and normal pigmentary variation phenotypes and melanoma. Only associations identified by GWAS and meeting the genomewide significance criterion (P < 5 × 10⁻⁸) are shown; associations claimed on the basis of candidate gene case-control studies are not included. RA, rheumatoid arthritis; T1D, type 1 diabetes mellitus; AITD, autoimmune thyroid disease; SLE, systemic lupus erythematosus; IBD, inflammatory bowel disease; MS, multiple sclerosis; MG, myasthenia gravis; AI hepatitis, autoimmune hepatitis.