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

Proceedings of the National Academy of Sciences of the United States of America
Masahiro HayashiRichard A Spritz

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 t...Continue Reading

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Citations

Oct 21, 2016·Current Opinion in Immunology·James P Strassner, John E Harris
Mar 21, 2017·Dermatologic Clinics·Richard A Spritz, Genevieve H L Andersen
Sep 17, 2016·F1000Research·Prashiela MangaSeth J Orlow
Jan 23, 2019·HLA : Immune Response Genetics·Thálitta H A LimaErick C Castelli
Sep 12, 2019·Biomolecules·Luciana Veiga-CastelliCelso Mendes-Junior
Oct 31, 2019·Expert Review of Clinical Immunology·Giulio Cavalli, Ennio Giulio Favalli
Nov 20, 2019·Pigment Cell & Melanoma Research·Genevieve H L RobertsRichard A Spritz
Dec 28, 2016·HLA : Immune Response Genetics·S Caillat-Zucman
Nov 22, 2018·Frontiers in Pharmacology·Giulio Cavalli, Charles A Dinarello
Oct 24, 2019·Genetic Testing and Molecular Biomarkers·Xianfa TangAnping Zhang
Jun 29, 2018·Frontiers in Immunology·Giacomo De LucaLorenzo Dagna
Oct 21, 2020·Expert Opinion on Drug Safety·Giulio CavalliLorenzo Dagna
Nov 18, 2020·Medicinal Research Reviews·Jianru ChenChunying Li
Aug 12, 2020·The Journal of Investigative Dermatology·Richard A Spritz, Stephanie A Santorico
Jan 7, 2021·The Journal of Dermatology·Christina Bergqvist, Khaled Ezzedine
Jan 13, 2021·International Journal of Clinical Practice·Yıldız HayranFüsun Özmen

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