The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma

Abstract

Generalized vitiligo (GV) is the most common pigmentation disease, in which white spots of skin and overlying hair result from loss of melanocytes from the involved regions. GV is a complex disease involving both genetic predisposition and unknown environmental triggers. Whereas various pathogenetic mechanisms have been suggested, most evidence supports an autoimmune basis for this disease. Recently, three different genome-wide association studies of GV have been reported, identifying a total of 17 confirmed GV susceptibility loci. Almost all of these genes encode immunoregulatory proteins, together highlighting pathways by which melanocytes might be recognized and killed. Moreover, the biological interaction between two of these GV susceptibility genes, HLA-A and TYR (encoding tyrosinase), points to an apparent inverse relationship between susceptibility to GV versus malignant melanoma, suggesting that GV may result, in part, from dysregulation of normal processes of immune surveillance against melanoma.

Figure 1

A patient with generalized vitiligo. Note the typical pattern of bilateral, multifocal depigmentation of hands and periorbital regions.

Figure 2

Genetic relationships of generalized vitiligo susceptibility genes and other autoimmune diseases. Circles indicate loci associated with susceptibility to a given autoimmune disease: yellow, shared risk alleles; orange, opposite risk alleles at same SNP; white, secondary association due to primary association with autoimmune disease epidemiologically associated with generalized vitiligo. SLE, systemic lupus erythematosus.