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Early-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression.


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.

SUBMITTER: Jin Y 

PROVIDER: S-EPMC6344500 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Early-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression.

Jin Ying Y   Roberts Genevieve H L GHL   Ferrara Tracey M TM   Ben Songtao S   van Geel Nanja N   Wolkerstorfer Albert A   Ezzedine Khaled K   Siebert Janet J   Neff Charles P CP   Palmer Brent E BE   Santorico Stephanie A SA   Spritz Richard A RA  

Nature communications 20190123 1


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, re  ...[more]

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