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

Ying Jin, Genevieve H. L. Roberts, Tracey M. Ferrara, Songtao Ben, Nanja Geel, Albert Wolkerstorfer, Khaled Ezzedine, Janet Siebert, Charles P. Neff, Brent E. Palmer, Stephanie A. Santorico and Richard A. Spritz ()
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Ying Jin: University of Colorado School of Medicine
Genevieve H. L. Roberts: University of Colorado School of Medicine
Tracey M. Ferrara: University of Colorado School of Medicine
Songtao Ben: University of Colorado School of Medicine
Nanja Geel: Ghent University Hospital
Albert Wolkerstorfer: Academic Medical Centre University of Amsterdam
Khaled Ezzedine: Université Paris-Est Créteil
Janet Siebert: CytoAnalytics
Charles P. Neff: University of Colorado School of Medicine
Brent E. Palmer: University of Colorado School of Medicine
Stephanie A. Santorico: University of Colorado School of Medicine
Richard A. Spritz: University of Colorado School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08337-4

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