We identified 10 independent susceptibility loci for generalized vitiligo. In general, these associations were observed in both the subgroup of patients with vitiligo only and the subgroup with vitiligo and concomitant autoimmune diseases (Table 4 in the Supplementary Appendix
(rs2476601) was the exception; the risk allele was significantly more prevalent among patients with generalized vitiligo and other autoimmune diseases. In the MHC region, we detected two major association signals, one in the class I gene region, between HLA-A
, and the other in the class II gene region, between HLA-DRB1
(). This finding is consistent with previous reports of an association of vitiligo with the HLA-A*02 allele16
and the HLA-DRB1*04 allele.15
Indeed, the near-perfect linkage disequilibrium between HLA-A*02 and the risk variant at rs12206499 suggests that HLA-A*02 may be the etiologic variant at this locus that confers susceptibility to vitiligo.
Outside the MHC, we identified signals of an association with generalized vitiligo within or near the RERE
, and C1QTNF6
, and C1QTNF6
are also associated with genetic susceptibility to other autoimmune diseases, several of which are epidemiologically associated with generalized vitiligo. These findings support the long-standing hypothesis that generalized vitiligo involves genetic susceptibility loci shared with other autoimmune diseases.3
Most of these genes encode immune-system proteins involved in biologic pathways that probably influence the development of autoimmunity.
In contrast, TYR
encodes tyrosinase, which is not a component of the immune system. Rather, it is an enzyme of the melanocyte that catalyzes the rate-limiting steps of melanin biosynthesis.32
It is also a major autoantigen in generalized vitiligo.1,2
Generalized vitiligo is thus genetically analogous to type 1 diabetes, in which variation in the INS
gene, encoding insulin (an important autoantigen in diabetes), contributes to disease susceptibility. Vitiligo is associated with the major alleles of SNPs in the TYR
region, particularly rs1393350 (in the combined analysis, P=1.60×10−18
; odds ratio, 1.53) and the nearby nonsynonymous (R402Q) SNP rs1126809 (Table 5 in the Supplementary Appendix
), with which rs1393350 is in tight linkage disequilibrium (Table 6 in the Supplementary Appendix
). The minor alleles of both these SNPs are associated with susceptibility to malignant melanoma,36,37
suggesting that susceptibility to TYR
-related generalized vitiligo and susceptibility to TYR
-related malignant melanoma are mediated by different or perhaps even inverse biologic mechanisms. The 402Q variant of the TYR protein (the variant associated with melanoma) is thermosensitive38
and at 37°C tends to be misfolded, aberrantly glycosylated, retained in the endoplasmic reticulum, and subject to proteosomal degradation,39
resulting in steady-state 402Q tyrosinase activity that is only 25% of that of the major 402R polypeptide (which is associated with susceptibility to generalized vitiligo).38
Correct glycosylation of tyrosinase augments the generation of an MHC class I–restricted tyrosinase epitope that is presented by HLA-A*0201,40
the predominant HLA-A*02 allele, and indeed, we detected significant epistasis between HLA-A
SNP rs12206499 and TYR
SNP rs1393350 (P=0.03).
Thus, 402R tyrosinase not only is expressed at higher levels than the 402Q variant but also may be more efficiently presented to the immune system by HLA-A*02. It is therefore plausible that the 402R variant makes a greater contribution than the 402Q variant to immune surveillance against neoplastic melanocytes and susceptibility to vitiligo. On the other hand, in persons carrying one or two copies of the 402Q variant, immune surveillance may fail to detect neoplastic melanocytes, owing to the reduced expression, and thus the reduced immune presentation, of tyrosinase.
Generally, there is limited correspondence between the associations shown in the present study and genetic linkage and candidate-gene association signals reported previously for generalized vitiligo,3
though a detailed analysis supported an association with NLRP1
in multiplex families and specific subgroups of patients (see the Supplementary Appendix
). Moreover, none of the significant associations reported in this study correspond to the principal up-regulated or down-regulated transcripts identified with the use of gene-expression profiling of melanocytes from patients with generalized vitiligo.41
Although the implicated loci that we have described here together account for only approximately 7.4% of the total genetic risk for generalized vitiligo, they provide insights into disease pathogenesis and implicate potential targets for therapeutic intervention.