Abstract
Vitiligo is an autoimmune disease in which melanocyte destruction causes skin depigmentation, with 49 loci known from previous GWAS. Aiming to define vitiligo subtypes, we discovered that age-of-onset is bimodal; one-third of cases have early onset (mean 10.3 years) and two-thirds later onset (mean 34.0 years). In the early-onset subgroup we found novel association with MHC class II region indel rs145954018, and independent association with the principal MHC class II locus from previous GWAS, represented by rs9271597; greatest association was with rs145954018del-rs9271597A haplotype (P = 2.40 × 10−86, OR = 8.10). Both rs145954018 and rs9271597 are located within lymphoid-specific enhancers, and the rs145954018del-rs9271597A haplotype is specifically associated with increased expression of HLA-DQB1 mRNA and HLA-DQ protein by monocytes and dendritic cells. Thus, for vitiligo, MHC regulatory variation confers extreme risk, more important than HLA coding variation. MHC regulatory variation may represent a significant component of genetic risk for other autoimmune diseases.
Highlights
Vitiligo is an autoimmune disease in which melanocyte destruction causes skin depigmentation, with 49 loci known from previous genome-wide association studies (GWAS)
In three previous genome-wide association studies (GWAS), we identified 49 genetic loci associated with vitiligo susceptibility[2,3,4,5,6], most of which harbor genes involved in regulation of immune cells, apoptosis, and melanocyte function
Vitiligo is frequently associated with other autoimmune diseases, autoimmune thyroid disease, type 1 diabetes, pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, and Addison disease[8], and a number of vitiligo susceptibility loci are shared with these other diseases[7]
Summary
Vitiligo is an autoimmune disease in which melanocyte destruction causes skin depigmentation, with 49 loci known from previous GWAS. In the early-onset subgroup we found novel association with MHC class II region indel rs145954018, and independent association with the principal MHC class II locus from previous GWAS, represented by rs9271597; greatest association was with rs145954018del-rs9271597A haplotype (P = 2.40 × 10−86, OR = 8.10). In the early-onset subgroup, we identify a novel, very strong association with rs145954018, an insertion-deletion (indel) polymorphism in the MHC class II region In both the early- and late-onset subgroups we observe independent association with a separate MHC class II locus found by our previous vitiligo GWAS, represented by rs9271597. For vitiligo, extreme genetic risk and early disease onset are genetically associated with a MHC class II haplotype that is associated with increased HLA-DQ expression, rather than with specific HLA alleles that produce structurally different HLA proteins
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