Vitiligo: An Update on Pathophysiology and Treatment Options

Reinhart Speeckaert; Nanja van Geel


Am J Clin Dermatol. 2017;18(6):733-744. 

In This Article

Heritability and Genes

The genetic origin of vitiligo is evident owing to the familial occurrence of vitiligo. First-grade relatives have a 6–8% risk of developing vitiligo. The concordance of vitiligo in monozygotic twins is approximately 23%.[15] This reflects the fact that vitiligo is a multi-genetic disease with a complex pathogenesis. In recent years, several genome-wide association studies have been conducted in vitiligo. These have identified that the large majority of genes associated with vitiligo exert an immunodulatory function while a minority of genes have been linked to melanocytes. A remarkable overlap of affected genes exists with other autoimmune disorders. For many identified susceptibility loci, the functional role in the pathogenesis of vitiligo is unknown. This underlines our incomplete knowledge of the pathogenesis.[16]

Several genes in the human leukocyte antigen region are associated with vitiligo. Association peaks have been discovered in the class I and II regions.[17] The human leukocyte antigen complex encodes for the major histocompatibility complex, which is responsible for the processing and presentation of antigens. The association between human leukocyte antigen types and autoimmune diseases can be explained by multiple pathways that ultimately lead to a derailed recognition of self-antigens. This results in the development of autoreactive T cells and/or failure to raise an efficient regulatory T-cell (Treg) population. Protein misfolding may occur, causing an unfolded protein stress response or the generation of autoantigens.[18]

A subset of immunoregulatory genes has been linked to vitiligo susceptibility. Genes encoding for factors involved in T-cell development and priming (e.g., CD44, CD80), T-cell receptor signaling (e.g., SLA, PTPN22, UBASH3A, CLNK), T-cell activation (e.g., IKZF4, IL2RA, BTNL2, FOXP3), the innate immune response (e.g., IFIH1, TICAM1), and chemokine or cytokine receptors (e.g., CXCR5, CCR6, SH2B3) have all been found to be associated with vitiligo in genome-wide association studies.[16,17,19,20]

Melanocytes also carry different genes related to the development of vitiligo. Several of these genes encode for proteins or enzymes that may serve as autoantigens (e.g., TYR, PMEL, MC1R, OCA2), facilitating the development of an anti-melanocyte immune response. Others are involved in the regulation of melanocyte development and survival (e.g., ZMIZ1), cell death during oxidative stress (e.g., RNASET2), and apoptosis (e.g., FGFR1OP). Other genes regulating apoptosis (e.g., RERE, CASP7) or immune-induced apoptosis (e.g., GZMB) have also been linked to vitiligo.[16]