title: Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo.
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-A*02:01, 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 gain-of-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers *02:01 specificity.
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Mathematical & Statistical Science, University of Colorado Denver, Denver, CO 80217;
authors.forename: Daniel
authors.initials: D
authors.lastname: Yorgov
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Mathematical & Statistical Science, University of Colorado Denver, Denver, CO 80217;
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Santorico
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: James
authors.initials: J
authors.lastname: Hagman
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Tracey M
authors.initials: TM
authors.lastname: Ferrara
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; Internal Medicine and Clinical Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute and Vita-Salute San Raffaele University, 20129 Milan, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cavalli
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; cdinare333@aol.com richard.spritz@ucdenver.edu.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045; cdinare333@aol.com richard.spritz@ucdenver.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D015234:HLA-A Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014820:Vitiligo / Q000235:genetics / Q000276:immunology*
chemical_list: D015234:HLA-A Antigens
keywords: HLA; autoimmune disease; enhancer; transcription; vitiligo