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Jin Y.,Aurora University | Birlea S.A.,Aurora University | Fain P.R.,Aurora University | Ferrara T.M.,Aurora University | And 25 more authors.
Nature Genetics | Year: 2012

We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis (3,187 cases and 6,723 controls) identifying 13 additional vitiligo-associated loci. These include OCA2-HERC2 (combined P = 3.80 × 10 -8), MC1R (P = 1.82 × 10 -13), a region near TYR (P = 1.57 × 10 -13), IFIH1 (P = 4.91 × 10 -15), CD80 (P = 3.78 × 10 -10), CLNK (P = 1.56 × 10 -8), BACH2 (P = 2.53 × 10 -8), SLA (P = 1.58 × 10 -8), CASP7 (P = 3.56 × 10 -8), CD44 (P = 1.78 × 10 -9), IKZF4 (P = 2.75 × 10 -14), SH2B3 (P = 3.54 × 10 -18) and TOB2 (P = 6.81 × 10 -10). Most vitiligo susceptibility loci encode immunoregulatory proteins or melanocyte components that likely mediate immune targeting and the relationships among vitiligo, melanoma, and eye, skin and hair coloration. © 2012 Nature America, Inc. All rights reserved.

Jin Y.,Aurora University | Birlea S.A.,Aurora University | Fain P.R.,Aurora University | Mailloux C.M.,Aurora University | And 15 more authors.
Nature Genetics | Year: 2010

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P = 1.04 × 10 8) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P = 3.94 × 10-7). © 2010 Nature America, Inc. All rights reserved.

Jin Y.,University of Colorado at Denver | Birlea S.A.,University of Colorado at Denver | Fain P.R.,University of Colorado at Denver | Gowan K.,University of Colorado at Denver | And 15 more authors.
Journal of Investigative Dermatology | Year: 2011

Generalized vitiligo is a common autoimmune disease in which acquired patchy depigmentation of skin, hair, and mucous membranes results from loss of melanocytes from involved areas. Previous genetic analyses have focused on vitiligo susceptibility, and have identified a number of genes involved in disease risk. Age of onset of generalized vitiligo also involves a substantial genetic component, but has not previously been studied systematically. In this study, we report a genome-wide association study of vitiligo age of onset in 1,339 generalized vitiligo patients, with replication in an independent cohort of 677 cases. We identified a quantitative trait locus for vitiligo age of onset in the major histocompatibility complex (MHC) class II region, located near c6orf10-BTNL2 (rs7758128; P8.14 × 10 11), a region that is also associated with generalized vitiligo susceptibility. In contrast, there was no association of vitiligo age of onset with any other MHC or non-MHC loci that are associated with vitiligo susceptibility. These findings highlight the differing roles played by genes involved in vitiligo susceptibility versus vitiligo age of onset, and illustrate that genome-wide analyses can be used to identify genes involved in quantitative aspects of disease natural history, as well as disease susceptibility per se. © 2011 British Association of Dermatologists.

Birlea S.A.,Aurora University | Jin Y.,Aurora University | Bennett D.C.,St George's, University of London | Herbstman D.M.,Florida College | And 11 more authors.
Journal of Investigative Dermatology | Year: 2011

We previously carried out a genome-wide association study of generalized vitiligo (GV) in non-Hispanic whites, identifying 13 confirmed susceptibility loci. In this study, we re-analyzed the genome-wide data set (comprising 1,392 cases and 2,629 controls) to specifically test association of all 33 GV candidate genes that have previously been suggested for GV, followed by meta-analysis incorporating both current and previously published data. We detected association of three of the candidate genes tested: TSLP (rs764916, P3.0E-04, odds ratio (OR)1.60; meta-P for rs38069333.1E-03), XBP1 (rs6005863, P3.6E-04, OR1.17; meta-P for rs22695779.5E-09), and FOXP3 (rs11798415, P5.8E-04, OR1.19). Association of GV with CTLA4 (rs12992492, P5.9E-05, OR1.20; meta-P for rs2317751.0E-04) seems to be secondary to epidemiological association with other concomitant autoimmune diseases. Within the major histocompatibility complex (MHC), at 6p21.33, association with TAP1-PSMB8 (rs3819721, P5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions. © 2011 The Society for Investigative Dermatology.

Jin Y.,Aurora University | Birlea S.A.,Aurora University | Fain P.R.,Aurora University | Fain P.R.,Barbara Davis Center for Childhood Diabetes | And 21 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. METHODS: To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. RESULTS: We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility- complex class I molecules (P = 9.05×10-23) and class II molecules (P = 4.50×10-34), PTPN22 (P = 1.31×10 -7), LPP (P = 1.01×10-11), IL2RA (P = 2.78×10-9), UBASH3A (P = 1.26×10-9), and C1QTNF6 (P = 2.21×10-16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P = 7.07×10-15) and GZMB (P = 3.44×10-8), and in a locus containing TYR (P = 1.60×10-18), encoding tyrosinase. CONCLUSIONS: We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma. Copyright © 2010 Massachusetts Medical Society.

PubMed | University of Amsterdam, Vitiligo Research Foundation, University of Colorado at Denver, Instituto Dermatologico San Gallicano and 14 more.
Type: Journal Article | Journal: Nature genetics | Year: 2016

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

Mosenson J.A.,Loyola University Chicago | Zloza A.,Rush University Medical Center | Zloza A.,Loyola University Chicago | Nieland J.D.,University of Aarhus | And 17 more authors.
Science Translational Medicine | Year: 2013

Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell-mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substratebinding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, andmutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A-encoding DNA applied months before spontaneous depigmentation prevented vitiligo inmice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70i Q435A therapeutically in a different, rapidly depigmentingmodel after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift fromquiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved.

Klarquist J.,Loyola University Chicago | Denman C.J.,Loyola University Chicago | Hernandez C.,University of Illinois at Chicago | Wainwright D.J.,Loyola University Chicago | And 5 more authors.
Pigment Cell and Melanoma Research | Year: 2010

In human vitiligo, cutaneous depigmentation involves cytotoxic activity of autoreactive T cells. It was hypothesized that depigmentation can progress in the absence of regulatory T cells (Treg). The percentage of Treg among skin infiltrating T cells was evaluated by immunoenzymatic double staining for CD3 and FoxP3, revealing drastically reduced numbers of Treg in non-lesional, perilesional and lesional vitiligo skin. Assessment of the circulating Treg pool by FACS analysis of CD4, CD25, CD127 and FoxP3 expression, and mixed lymphocyte reactions in presence and absence of sorted Treg revealed no systemic drop in the abundance or activity of Treg in vitiligo patients. Expression of skin homing receptors CCR4, CCR5, CCR8 and CLA was comparable among circulating vitiligo and control Treg. Treg from either source were equally capable of migrating towards CCR4 ligand and skin homing chemokine CCL22, yet significantly reduced expression of CCL22 in vitiligo skin observed by immunohistochemistry may explain failure of circulating, functional Treg to home to the skin in vitiligo. The paucity of Treg in vitiligo skin is likely crucial for perpetual anti-melanocyte reactivity in progressive disease.

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