Genetic Factors
Genetic involvement in vitiligo is obvious from a simple examination of family histories: 15-20% of vitiligo patients have at least one affected first-grade relative [165]. However, vitiligo does not show a Mendelian mechanism of inheritance, but is the polygenic with multiple susceptibility loci [147]. The concordance rate in monozygotic twins is 23%, suggesting involvement of non-genetic factors [166]. Genome-wide association studies have revealed that approximately half of vitiligo susceptibility genes encode immune-regulatory proteins, while the remainder encode melanocyte-specific proteins [147]. Several studies have shown that multiple loci contribute to vitiligo susceptibility (Table 1) . An observed association between HLA types and vitiligo, and other autoimmune disorders, can be elucidated by several pathways that ultimately result in disruption in self-antigen recognition (Jin et al., 2012a). This can lead to autoreactive T cell development and/or failure to produce effective Tregs population [60]. Genome-wide association studies have also reported a subset of other immune regulatory genes that are also key mediators of adaptive immunity such as CD80 (activation of T cells), cytotoxic T lymphocyte antigen-4; CTLA4 (inhibition of T cells), GZMB(cytotoxicity of T cells), forkhead box protein P3; FOXP3(development and function of regulatory T cells), lymphoid protein tyrosine phosphatase non-receptor type 22; PTPN22(down-regulation of T cell activation) and arginine–glutamic acid dipeptide repeats protein; RERE (regulation of cell apoptosis) [167]. An association of vitiligo with genes that play a role in innate immunity, such as NACHT leucine-rich-repeat protein 1 (NLRP1 ), interferon-induced helicase C domain 1 (IFIH1 ) and caspase-7 (CASP7 ), has also been found in genome-wide association studies [168]. In addition to immune regulatory genes, several genes that are only expressed in melanocytes and involved in melanocyte function have been identified as vitiligo susceptibility loci. These include TYR , PMEL , melanocortin 1 receptor (MC1R ), OCA2 [169]. Such genes encode for enzymes or proteins recognised as autoantigens in vitiligo, facilitating an anti-melanocyte autoimmune response [122, 124].