Title

Autoimmune vitiligo is associated with gain-offunction by a transcriptional regulator that elevates expression of HLA-A∗02:01 in vivo

Document Type

Article

Publication Date

2-2016

Publication Source

Proceedings of the National Academy of Sciences of the United States of America

Volume

113

Issue

5

Inclusive pages

1357-1362

DOI

10.1073/pnas.1525001113

Publisher

National Academy of Sciences

ISBN/ISSN

0027-8424

Peer Reviewed

yes

Abstract

HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A02:01, which presents multiple vitiligo melanocyte autoantigens. Refined genetic mapping localizes vitiligo risk in the HLA-A region to an SNP haplotype ∼20-kb downstream, spanning an ENCODE element with many characteristics of a transcriptional enhancer. Convergent CTCF insulator sites flanking the HLA-A gene promoter and the predicted transcriptional regulator, with apparent interaction between these sites, suggests this element regulates the HLA-A promoter. Peripheral blood mononuclear cells from healthy subjects homozygous for the high-risk haplotype expressed 39% more HLA-A RNA than cells from subjects carrying nonhigh-risk haplotypes (P = 0.0048). Similarly, RNAseq analysis of 1,000 Genomes Project data showed more HLA-A mRNA expressed in subjects homozygous for the high-risk allele of lead SNP rs60131261 than subjects homozygous for the low-risk allele (P = 0.006). Reporter plasmid transfection and genomic run-on sequence analyses confirm that the HLA-A transcriptional regulator contains multiple bidirectional promoters, with greatest activity on the high-risk haplotype, although it does not behave as a classic enhancer. Vitiligo risk associated with the MHC class I region thus derives from combined quantitative and qualitative phenomena: a SNP haplotype in a transcriptional regulator that induces gainof-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers 02:01 specificity.

Keywords

allele, Article, cell surface, controlled study, DNA flanking region, enhancer region, gain of function mutation, gene linkage disequilibrium, gene mapping, genetic transfection, haplotype, high risk patient, homozygote, human, human cell, in vivo study, major clinical study, peripheral blood mononuclear cell, priority journal, promoter region, qualitative analysis, quantitative analysis, risk factor, sequence analysis, single nucleotide polymorphism, transcription regulation, HLA A antigen, major histocompatibility antigen class 1, messenger RNA, Autoimmune disease, Enhancer, HLA, Transcription, Vitiligo

Disciplines

Mathematics

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