TY - JOUR
T1 - Early-onset autoimmune vitiligo associated with an enhancer variant haplotype that upregulates class II HLA expression
AU - Jin, Ying
AU - Roberts, Genevieve H. L.
AU - Ferrara, Tracey M.
AU - Ben, Songtao
AU - van Geel, Nanja
AU - Wolkerstorfer, Albert
AU - Ezzedine, Khaled
AU - Siebert, Janet
AU - Neff, Charles P.
AU - Palmer, Brent E.
AU - Santorico, Stephanie A.
AU - Spritz, Richard A.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85060374507&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30674883
U2 - 10.1038/s41467-019-08337-4
DO - 10.1038/s41467-019-08337-4
M3 - Article
C2 - 30674883
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 391
ER -