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1.
J Invest Dermatol ; 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38848986

ABSTRACT

A better understanding of human melanocyte (MC) and melanocyte stem cell (McSC) biology is essential for treating melanocyte-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate the SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical exams, human cell assays, yeast two-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in McSC maintenance and discovered that TNKS2 is crucial for SASH1's role. Additionally, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human McSC. The findings offer insights into the roles of SASH1 and TNKS2 in McSC maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.

2.
Pigment Cell Melanoma Res ; 37(3): 378-390, 2024 May.
Article in English | MEDLINE | ID: mdl-38343115

ABSTRACT

We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/ß-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.


Subject(s)
Epidermis , Melanocytes , Skin Pigmentation , Vitiligo , Vitiligo/pathology , Vitiligo/radiotherapy , Vitiligo/metabolism , Humans , Epidermis/pathology , Epidermis/metabolism , Epidermis/radiation effects , Skin Pigmentation/radiation effects , Melanocytes/pathology , Melanocytes/metabolism , Melanocytes/radiation effects , Ultraviolet Therapy/methods , Keratinocytes/metabolism , Keratinocytes/pathology , Keratinocytes/radiation effects , Ultraviolet Rays , Female , Male , Wnt Signaling Pathway , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics
3.
bioRxiv ; 2023 Sep 27.
Article in English | MEDLINE | ID: mdl-37808724

ABSTRACT

Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1 S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1 S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1's promotion of stem-like function. Further, the SASH1 S519N variant is in a bona fide Tankyrase-binding motif, and SASH1 S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.

4.
J Invest Dermatol ; 141(3): 638-647.e13, 2021 03.
Article in English | MEDLINE | ID: mdl-32800877

ABSTRACT

In repigmentation of human vitiligo, the melanocyte (MC) precursors in the hair follicle bulge proliferate, migrate, and differentiate to repopulate the depigmented epidermis. Here, we present a comprehensive characterization of pathways and signals in the bulge that control the repigmentation process. Using biopsies from patients with vitiligo, we have selectively harvested, by laser capture microdissection, MC and keratinocyte precursors from the hair follicle bulge of untreated vitiligo skin and vitiligo skin treated with narrow-band UVB. The captured material was subjected to whole transcriptome RNA-sequencing. With this strategy, we found that repigmentation in the bulge MC precursors is driven by KCTD10, a signal with unknown roles in the skin, and CTNNB1 (encoding ß-catenin) and RHO guanosine triphosphatase [RHO GTPase, RHO], two signaling pathways previously shown to be involved in pigmentation biology. Knockdown studies in cultured human MCs of RHOJ, the upmost differentially expressed RHO family component, corroborated with our findings in patients with vitiligo, identified RHOJ involvement in UV response and melanization, and confirmed previously identified roles in melanocytic cell migration and apoptosis. A better understanding of mechanisms that govern repigmentation in MC precursors will enable the discovery of molecules that induce robust repigmentation phenotypes in vitiligo.


Subject(s)
Adult Stem Cells/metabolism , Melanocytes/metabolism , Skin Pigmentation/radiation effects , Ultraviolet Therapy , Vitiligo/therapy , Adolescent , Adult , Adult Stem Cells/radiation effects , Aged , Child , Female , Hair Follicle/cytology , Hair Follicle/metabolism , Hair Follicle/pathology , Hair Follicle/radiation effects , Humans , Keratinocytes/metabolism , Keratinocytes/radiation effects , Male , Melanocytes/radiation effects , Middle Aged , Potassium Channels, Voltage-Gated/metabolism , RNA-Seq , Signal Transduction/radiation effects , Treatment Outcome , Vitiligo/pathology , Young Adult , beta Catenin/metabolism , rho GTP-Binding Proteins/metabolism
5.
J Invest Dermatol ; 140(1): 29-37, 2020 01.
Article in English | MEDLINE | ID: mdl-31196751

ABSTRACT

Vitiligo and alopecia areata (AA) are common autoimmune conditions characterized by white spots on the skin (vitiligo) and bald spots on the scalp (AA), which significantly impact patients' lives by damaging their appearance and function. Melanocytes are the target of immune destruction in vitiligo and are hypothesized to be the site of immune attack in AA. This inflammatory process can be partially reversed by immunosuppressive drugs. Both conditions demonstrate regenerative components that are just now being identified. In this review, we focus on the regenerative medicine aspects of vitiligo and AA, using experimental data from human, mouse, and in vitro models, summarizing the key pathways involved in repopulation of the epidermis with melanocytes in vitiligo and in regrowth of hair follicles in AA. We also discuss treatments that may activate these pathways. Of the regenerative treatments, JAK inhibitors and bimatoprost stimulate repopulation of depleted cells in both diseases, intralesional injections of autologous concentrated platelet-rich plasma and minoxidil showed some benefit in AA, and phototherapy with narrowband UVB was shown to be effective especially in vitiligo. Finally, we discuss future treatments based on the mobilization of stem cells to regenerate anagen hair follicles in AA and intraepidermal melanocytes in vitiligo.


Subject(s)
Alopecia Areata/therapy , Bimatoprost/therapeutic use , Guided Tissue Regeneration/methods , Hair Follicle/physiology , Janus Kinase Inhibitors/therapeutic use , Melanocytes/physiology , Vitiligo/therapy , Animals , Cell Movement , Cell Self Renewal , Humans , Mice , Phototherapy , Regenerative Medicine
6.
Pigment Cell Melanoma Res ; 31(6): 728-735, 2018 11.
Article in English | MEDLINE | ID: mdl-30281213

ABSTRACT

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology. Significantly, this document encapsulates important advances in melanocyte and melanoma research including emerging frontiers in melanoma immunotherapy, medical and surgical oncology, dermatology, vitiligo, albinism, genomics and systems biology, epidemiology, pigment biophysics and chemistry, and evolution.


Subject(s)
Biomedical Research , Melanocytes/pathology , Melanoma/pathology , Animals , Disease Models, Animal , Drug Resistance, Neoplasm , Humans , Melanoma/epidemiology , Melanoma/prevention & control , Melanoma/therapy , Pigmentation
8.
J Invest Dermatol ; 138(3): 657-668, 2018 03.
Article in English | MEDLINE | ID: mdl-29054607

ABSTRACT

Vitiligo repigmentation is a complex process in which the melanocyte-depleted interfollicular epidermis is repopulated by melanocyte precursors from hair follicle bulge that proliferate, migrate, and differentiate into mature melanocytes on their way to the epidermis. The strongest stimulus for vitiligo repigmentation is narrow-band UVB (NBUVB), but how the hair follicle melanocyte precursors are activated by UV light has not been extensively studied. To better understand this process, we developed an application that combined laser capture microdissection and subsequent whole transcriptome RNA sequencing of hair follicle bulge melanocyte precursors and compared their gene signatures to that of regenerated mature epidermal melanocytes from NBUVB-treated vitiligo skin. Using this strategy, we found up-regulation of TNC, GJB6, and THBS1 in the hair follicle bulge melanocytes and of TYR in the epidermal melanocytes of the NBUVB-treated vitiligo skin. We validated these results by quantitative real-time-PCR using NBUVB-treated vitiligo skin and untreated normal skin. We also identified that GLI1, a candidate stem cell-associated gene, is significantly up-regulated in the melanocytes captured from NBUVB-treated vitiligo bulge compared with untreated vitiligo bulge. These signals are potential key players in the activation of bulge melanocyte precursors during vitiligo repigmentation.


Subject(s)
Hair Follicle/cytology , Signal Transduction/physiology , Skin Pigmentation , Stem Cells/metabolism , Ultraviolet Therapy , Vitiligo/radiotherapy , Zinc Finger Protein GLI1/genetics , beta Catenin/physiology , Humans , Laser Capture Microdissection , Sequence Analysis, RNA , Transcription, Genetic
9.
J Invest Dermatol ; 137(7): 1408-1410, 2017 07.
Article in English | MEDLINE | ID: mdl-28647026

ABSTRACT

Vitiligo, the most common depigmenting disorder, is caused by immune destruction of melanocytes by cytotoxic CD8+ T cells. One weakness in vitiligo management is the lack of an assessment method for active depigmentation. Beginning with reports about increased S100B levels in different inflammatory and tissue damage processes, Speeckaert et al. explored correlations between the S100B dynamics and vitiligo activity, identifying high circulating S100B levels in patients with active depigmentation which were strongly correlated with the extent of affected skin surface. These authors have proposed S100B as a potential disease activity marker in vitiligo.


Subject(s)
Autoimmunity , S100 Calcium Binding Protein beta Subunit/metabolism , Skin/pathology , Vitiligo , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Humans , Melanocytes/immunology , Melanocytes/metabolism , Melanocytes/pathology , Vitiligo/immunology , Vitiligo/metabolism , Vitiligo/pathology
10.
Dermatol Clin ; 35(2): 205-218, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28317529

ABSTRACT

Repigmentation in vitiligo is the process that replaces, in the epidermal basal layer of vitiligo skin, the mature melanocytes that have been killed by cytotoxic T cells specific for melanocyte antigens. It consists of mobilization of melanocyte precursors in the hair follicle bulge and infundibulum to proliferate, migrate, and differentiate into mature melanocytes, moving from the hair follicle bulge to the interfollicular epidermis. The most common clinical presentation of repigmentation in vitiligo is the perifollicular pattern. The most potent stimulus for repigmentation is the UV light.


Subject(s)
Melanocytes , Regeneration , Ultraviolet Therapy , Vitiligo/therapy , Epidermal Cells , Hair Follicle/cytology , Humans , Keratinocytes , PUVA Therapy
11.
Med Res Rev ; 37(4): 907-935, 2017 07.
Article in English | MEDLINE | ID: mdl-28029168

ABSTRACT

Vitiligo is the most frequent human pigmentary disorder, characterized by progressive autoimmune destruction of mature epidermal melanocytes. Of the current treatments offering partial and temporary relief, ultraviolet (UV) light is the most effective, coordinating an intricate network of keratinocyte and melanocyte factors that control numerous cellular and molecular signaling pathways. This UV-activated process is a classic example of regenerative medicine, inducing functional melanocyte stem cell populations in the hair follicle to divide, migrate, and differentiate into mature melanocytes that regenerate the epidermis through a complex process involving melanocytes and other cell lineages in the skin. Using an in-depth correlative analysis of multiple experimental and clinical data sets, we generated a modern molecular research platform that can be used as a working model for further research of vitiligo repigmentation. Our analysis emphasizes the active participation of defined molecular pathways that regulate the balance between stemness and differentiation states of melanocytes and keratinocytes: p53 and its downstream effectors controlling melanogenesis; Wnt/ß-catenin with proliferative, migratory, and differentiation roles in different pigmentation systems; integrins, cadherins, tetraspanins, and metalloproteinases, with promigratory effects on melanocytes; TGF-ß and its effector PAX3, which control differentiation. Our long-term goal is to design pharmacological compounds that can specifically activate melanocyte precursors in the hair follicle in order to obtain faster, better, and durable repigmentation.


Subject(s)
Melanocytes/pathology , Regenerative Medicine/methods , Stem Cells/pathology , Vitiligo/therapy , Animals , Humans , Melanocytes/drug effects , Regenerative Medicine/trends , Stem Cells/drug effects , Vitiligo/drug therapy , Vitiligo/pathology
12.
Nat Genet ; 48(11): 1418-1424, 2016 11.
Article in English | MEDLINE | ID: mdl-27723757

ABSTRACT

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.


Subject(s)
Autoimmune Diseases/genetics , Genetic Predisposition to Disease , Vitiligo/genetics , Female , Genome-Wide Association Study , Genotype , Humans , Male , Melanoma/genetics , Quantitative Trait Loci , Risk Assessment
13.
Exp Dermatol ; 25(10): 805-11, 2016 10.
Article in English | MEDLINE | ID: mdl-27193292

ABSTRACT

To characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody, which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analysed by qRT-PCR. The melanocyte-specific gene transcripts TYR, DCT, TYRP1 and PMEL were significantly upregulated in our NBUVB-treated melanocyte samples as compared with the keratinocyte samples, while keratinocyte-specific genes (KRT5 and KRT14) were expressed significantly higher in the keratinocyte samples as compared with the melanocyte samples. Furthermore, in both NBUVB-treated vitiligo skin and normal skin, when bulge melanocytes were compared with epidermal melanocytes, we found significantly lower expression of melanocyte-specific genes and significantly higher expression of three melanocytic stem cell genes (SOX9, WIF1 and SFRP1), while ALCAM and ALDH1A1 transcripts did not show significant variation. We found significantly higher expression of melanocyte-specific genes in the epidermis of NBUVB-treated vitiligo, as compared to the normal skin. When comparing bulge melanocyte samples from untreated vitiligo, NBUVB-treated vitiligo and normal skin, we did not find significant differences in the expression of melanocyte-specific genes or melanocytic stem cell genes. These techniques offer valuable opportunities to study melanocytes and their precursors in vitiligo and other pigmentation disorders.


Subject(s)
Laser Capture Microdissection , Melanocytes/metabolism , RNA/isolation & purification , Vitiligo/metabolism , Case-Control Studies , Humans , RNA/metabolism , Vitiligo/radiotherapy
14.
J Invest Dermatol ; 135(8): 2068-2076, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25822579

ABSTRACT

In vitiligo, the autoimmune destruction of epidermal melanocytes produces white spots that can be repigmented by melanocyte precursors from the hair follicles, following stimulation with UV light. We examined by immunofluorescence the distribution of melanocyte markers (C-KIT, DCT, PAX3, and TYR) coupled with markers of proliferation (KI-67) and migration (MCAM) in precursors and mature melanocytes from the hair follicle and the epidermis of untreated and narrow band UVB (NBUVB)-treated human vitiligo skin. NBUVB was associated with a significant increase in the number of melanocytes in the infundibulum and with restoration of the normal melanocyte population in the epidermis, which was lacking in the untreated vitiligo. We identified several precursor populations (melanocyte stem cells, melanoblasts, and other immature phenotypes), and progressively differentiating melanocytes, some with putative migratory and/or proliferative abilities. The primary melanocyte germ was present in the untreated and treated hair follicle bulge, whereas a possible secondary melanocyte germ composed of C-KIT+ melanocytes was found in the infundibulum and interfollicular epidermis of UV-treated vitiligo. This is an exceptional model for studying the mobilization of melanocyte stem cells in human skin. Improved understanding of this process is essential for designing better treatments for vitiligo, ultimately based on melanocyte stem cell activation and mobilization.


Subject(s)
Melanocytes/pathology , Stem Cells/pathology , Ultraviolet Rays , Ultraviolet Therapy , Vitiligo/pathology , Vitiligo/radiotherapy , Cell Differentiation/radiation effects , Cell Movement/radiation effects , Cell Proliferation/radiation effects , Epidermis/metabolism , Epidermis/pathology , Epidermis/radiation effects , Hair Follicle/metabolism , Hair Follicle/pathology , Hair Follicle/radiation effects , Humans , Intramolecular Oxidoreductases/metabolism , Melanocytes/metabolism , Melanocytes/radiation effects , PAX3 Transcription Factor , Paired Box Transcription Factors/metabolism , Phenotype , Proto-Oncogene Proteins c-kit/metabolism , Stem Cells/metabolism , Stem Cells/radiation effects , Vitiligo/metabolism
15.
J Clin Invest ; 123(10): 4390-404, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23999427

ABSTRACT

Squamous cell carcinomas (SCCs) originate in stratified epithelia, with a small subset becoming metastatic. Epithelial stem cells are targets for driver mutations that give rise to SCCs, but it is unknown whether they contribute to oncogenic multipotency and metastasis. We developed a mouse model of SCC by targeting two frequent genetic mutations in human SCCs, oncogene Kras(G12D) activation and Smad4 deletion, to mouse keratin 15-expressing (K15+) stem cells. We show that transgenic mice developed multilineage tumors, including metastatic SCCs. Among cancer stem cell-enriched (CSC-enriched) populations, those with increased side population (SP) cells correlated with epithelial-mesenchymal transition (EMT) and lung metastasis. We show that microRNA-9 (miR-9) contributed to SP expansion and metastasis, and miR-9 inhibition reduced the number of SP cells and metastasis. Increased miR-9 was detected in metastatic human primary SCCs and SCC metastases, and miR-9-transduced human SCC cells exhibited increased invasion. We identified α-catenin as a predominant miR-9 target. Increased miR-9 in human SCC metastases correlated with α-catenin loss but not E-cadherin loss. Our results demonstrate that stem cells with Kras(G12D) activation and Smad4 depletion can produce tumors that are multipotent and susceptible to EMT and metastasis. Additionally, tumor initiation and metastatic properties of CSCs can be uncoupled, with miR-9 regulating the expansion of metastatic CSCs.


Subject(s)
Carcinoma, Squamous Cell/secondary , Neoplastic Stem Cells/pathology , Proto-Oncogene Proteins/genetics , Skin Neoplasms/pathology , Smad4 Protein/genetics , ras Proteins/genetics , Animals , Carcinogenesis/metabolism , Carcinoma, Squamous Cell/genetics , Cell Dedifferentiation , Cell Proliferation , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Nude , Mice, Transgenic , MicroRNAs/genetics , Mutation, Missense , Neoplasm Transplantation , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/physiology , Proto-Oncogene Proteins p21(ras) , RNA Interference , Sequence Deletion , Side-Population Cells/metabolism , Side-Population Cells/pathology , Side-Population Cells/physiology , Skin Neoplasms/genetics , Tumor Cells, Cultured , alpha Catenin/genetics , alpha Catenin/metabolism
16.
J Dermatol Sci ; 72(2): 168-76, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23867358

ABSTRACT

BACKGROUND: The effects of retinoids on melanogenesis and their mechanism as depigmenting agents in topical therapy have not been fully elucidated. Conflicting data about their impact on melanogenic pathways have been reported. OBJECTIVE: To investigate the effects of all-trans-retinoic acid (ATRA) on normal human melanocytes from Caucasian subjects. METHODS: We assessed ATRA's cytotoxicity by measuring viability with a cell proliferation assay, and apoptotic effects using Annexin V and γ-H2AX markers. ATRA's melanogenic activity was investigated based on spectrophotometric measurement of melanin content and tyrosinase enzymatic activity. Tyrosinase expression was assessed by Western blotting. We tested the antioxidant activity of superoxide dismutase (SOD) and catalase (CAT) in melanocytes using a spectrophotometric assay. RESULTS: Of the concentrations tested in this 72h time-course study, the 1.0µM ATRA had a well-defined two-stage pro-melanogenic and pro-apoptotic effect on melanocytes. In the first 6h, treated cells showed significant increase (p≤0.01) of melanin content, tyrosinase, SOD, and CAT activities compared to the controls. While overall tyrosinase expression was not affected by ATRA, all other tested parameters decreased progressively beyond the short-term point of 6h. ATRA treatment of over 6h induced melanocyte apoptosis, as shown by the time-dependent decrease in cell viability, coupled with significant increase in Annexin V positive cells and nuclear accumulation of γ-H2AX foci. CONCLUSION: The results obtained using this testing platform show a biphasic ATRA action: immediate pro-melanogenic effect and longer-term exposure pro-apoptotic activity. These data qualify ATRA as a potent tool to better understand the mechanisms that regulate the pigmentary system.


Subject(s)
Apoptosis , Melanocytes/drug effects , Tretinoin/pharmacology , Administration, Topical , Adult , Annexin A5/metabolism , Antioxidants/metabolism , Catalase/metabolism , Cell Proliferation , Cell Survival , Cells, Cultured , Histones/metabolism , Humans , Melanins/metabolism , Melanocytes/cytology , Melanocytes/metabolism , Microscopy, Phase-Contrast , Monophenol Monooxygenase/metabolism , Phenotype , Spectrophotometry , Superoxide Dismutase/metabolism , Time Factors , Young Adult
18.
Nat Genet ; 44(6): 676-80, 2012 May 06.
Article in English | MEDLINE | ID: mdl-22561518

ABSTRACT

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.


Subject(s)
Genetic Loci , Genetic Predisposition to Disease , Vitiligo/genetics , Chromosomes, Human, Pair 15 , Eye Color , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide
19.
J Invest Dermatol ; 131(6): 1308-12, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21326295

ABSTRACT

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; P=8.14 × 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.


Subject(s)
Genes, MHC Class II , Genome-Wide Association Study , Quantitative Trait Loci , Vitiligo/genetics , Adult , Age of Onset , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Proportional Hazards Models
20.
J Invest Dermatol ; 131(2): 371-81, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21085187

ABSTRACT

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, P=3.0E-04, odds ratio (OR)=1.60; meta-P for rs3806933=3.1E-03), XBP1 (rs6005863, P=3.6E-04, OR=1.17; meta-P for rs2269577=9.5E-09), and FOXP3 (rs11798415, P=5.8E-04, OR=1.19). Association of GV with CTLA4 (rs12992492, P=5.9E-05, OR=1.20; meta-P for rs231775=1.0E-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, P=5.2E-06) seems to derive from linkage disequilibrium with major primary signals in the MHC class I and class II regions.


Subject(s)
Cytokines/genetics , DNA-Binding Proteins/genetics , Forkhead Transcription Factors/genetics , Transcription Factors/genetics , Vitiligo/genetics , Case-Control Studies , Genetic Predisposition to Disease/genetics , Humans , Linkage Disequilibrium/genetics , Polymorphism, Single Nucleotide/genetics , Regulatory Factor X Transcription Factors , X-Box Binding Protein 1 , Thymic Stromal Lymphopoietin
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