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Mokhtari M, Bardhi R, Hamzavi I. A Canvas of Contemporary Insights into Clinical Vitiligo. Dermatol Clin 2025; 43:67-76. [PMID: 39542565 DOI: 10.1016/j.det.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024]
Abstract
Vitiligo is a chronic skin condition characterized by the loss of melanocytes, resulting in white patches on the skin. While its exact cause is unknown, it's believed to be an autoimmune disorder involving genetic, environmental, and immunologic factors. Various treatments, including topical drugs, phototherapy, and surgery, exist, but further research is needed for more targeted therapies. Standardization of treatment goals and outcome measures is crucial. Future directions involve personalized treatments based on genetic and immunologic profiles, along with advancements in melanocyte biology for more effective therapies. Collaborative research is the key to improving outcomes and quality of life for vitiligo patients.
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Affiliation(s)
- Mohsen Mokhtari
- Henry W. Lim Division of Photomedicine and Photobiology, Department of Dermatology, Multicultural Dermatology Center, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202, USA
| | - Redina Bardhi
- Henry W. Lim Division of Photomedicine and Photobiology, Department of Dermatology, Multicultural Dermatology Center, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202, USA
| | - Iltefat Hamzavi
- Henry W. Lim Division of Photomedicine and Photobiology, Department of Dermatology, Multicultural Dermatology Center, Henry Ford Health, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
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2
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Lu J, Song L, Luan J, Feng Y, Wang Y, Cao X, Lu Y. Identification of Shared Biomarkers and Immune Infiltration Signatures between Vitiligo and Hashimoto's Thyroiditis. Clin Cosmet Investig Dermatol 2024; 17:311-327. [PMID: 38327551 PMCID: PMC10847670 DOI: 10.2147/ccid.s451080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/23/2024] [Indexed: 02/09/2024]
Abstract
Background Vitiligo and Hashimoto's thyroiditis (HT) are concomitant autoimmune diseases characterized by the destruction of melanocytes or thyrocytes. We aimed to explore the immunological mechanism of this comorbidity and screen their potential biomarkers. Methods We downloaded the microarray datasets from the GEO database. Differentially expressed genes (DEGs) and immune-related genes (IRGs) were selected. The immune-related differentially expressed genes (IRDEGs) were obtained by taking the intersection. Candidate biomarkers were elected by Cytoscape software. CIBERSORT was used to depict immune cell infiltration prospects. Correlation analysis was conducted between infiltrating cells and several indicators. The results were validated by real-time quantitative PCR (RT-qPCR). Results Three datasets and 60 IRDEGs were obtained in total. Pathway enrichment analysis showed that the T cell receptor signaling pathway, IL-17 signaling pathway, receptor-ligand activity, and signaling receptor activator activity were significantly enriched. We screened out four hub genes, including IFNG, STAT1, IL1B, and CXCL10. The ROC curve indicated the highest diagnostic value of CXCL10 in both vitiligo and HT. Immuno-infiltration analysis revealed significant changes in T cell subsets and macrophage subtypes, which were correlated with four hub genes, melanocyte markers, and thyroid-specific antigens. qPCR validated the hub genes in peripheral blood mononuclear cells from patients with comorbidity. Conclusion IFNG, STAT1, IL1B, and CXCL10, were the key IRDEGs to vitiligo and HT. These genes may participate in the comorbidity by remodeling the immune cell infiltration pattern, and cross-expressed antigens may mediate the common damage of melanocytes and thyroid tissues.
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Affiliation(s)
- Jiawei Lu
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Lebin Song
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Jiaochen Luan
- Department of Urology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yifei Feng
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yidan Wang
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Xuechen Cao
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
| | - Yan Lu
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China
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3
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Li HOY, Bailey AMJ, Pastukhova E, Tan MG, Kirchhof MG. Comorbid diagnosis of systemic lupus erythematosus in vitiligo: a systematic review and meta-analysis. Br J Dermatol 2023; 188:440-441. [PMID: 36680305 DOI: 10.1093/bjd/ljac038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 08/29/2022] [Accepted: 11/26/2022] [Indexed: 01/22/2023]
Affiliation(s)
- Heidi Oi-Yee Li
- Division of Dermatology, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada
| | | | | | - Marcus G Tan
- Division of Dermatology, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada
| | - Mark G Kirchhof
- Division of Dermatology, University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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4
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Marchioro HZ, Castro CCSD, Fava VM, Sakiyama PH, Dellatorre G, Miot HA. Update on the pathogenesis of vitiligo. An Bras Dermatol 2022; 97:478-490. [PMID: 35643735 PMCID: PMC9263675 DOI: 10.1016/j.abd.2021.09.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/15/2021] [Accepted: 09/21/2021] [Indexed: 11/16/2022] Open
Abstract
Vitiligo is a complex disease whose pathogenesis results from the interaction of genetic components, metabolic factors linked to cellular oxidative stress, melanocyte adhesion to the epithelium, and immunity (innate and adaptive), which culminate in aggression against melanocytes. In vitiligo, melanocytes are more sensitive to oxidative damage, leading to the increased expression of proinflammatory proteins such as HSP70. The lower expression of epithelial adhesion molecules, such as DDR1 and E-cadherin, facilitates damage to melanocytes and exposure of antigens that favor autoimmunity. Activation of the type 1-IFN pathway perpetuates the direct action of CD8+ cells against melanocytes, facilitated by regulatory T-cell dysfunction. The identification of several genes involved in these processes sets the stage for disease development and maintenance. However, the relationship of vitiligo with environmental factors, psychological stress, comorbidities, and the elements that define individual susceptibility to the disease are a challenge to the integration of theories related to its pathogenesis.
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5
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The Genetics of Pediatric Cutaneous Autoimmunity: The Sister Diseases Vitiligo and Alopecia Areata. Clin Dermatol 2022; 40:363-373. [DOI: 10.1016/j.clindermatol.2022.02.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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6
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Dwivedi M, Laddha NC, Begum R. The Immunogenetics of Vitiligo: An Approach Toward Revealing the Secret of Depigmentation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:61-103. [PMID: 35286692 DOI: 10.1007/978-3-030-92616-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Vitiligo is a hypomelanotic skin disease and considered to be of autoimmune origin due to breaching of immunological self-tolerance, resulting in inappropriate immune responses against melanocytes. The development of vitiligo includes a strong heritable component. Different strategies ranging from linkage studies to genome-wide association studies are used to explore the genetic factors responsible for the disease. Several vitiligo loci containing the respective genes have been identified which contribute to vitiligo and genetic variants for some of the genes are still unknown. These genes include mainly the proteins that play a role in immune regulation and a few other genes important for apoptosis and regulation of melanocyte functions. Despite the available data on genetic variants and risk alleles which influence the biological processes, only few immunological pathways have been found responsible for all ranges of severity and clinical manifestations of vitiligo. However, studies have concluded that vitiligo is of autoimmune origin and manifests due to complex interactions in immune components and their inappropriate response toward melanocytes. The genes involved in the immune regulation and processing the melanocytes antigen and its presentation can serve as effective immune-therapeutics that can target specific immunological pathways involved in vitiligo. This chapter highlights those immune-regulatory genes involved in vitiligo susceptibility and loci identified to date and their implications in vitiligo pathogenesis.
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Affiliation(s)
- Mitesh Dwivedi
- C. G. Bhakta Institute of Biotechnology, Uka Tarsadia University, Tarsadi, Surat, 394350, Gujarat, India.
| | - Naresh C Laddha
- In Vitro Specialty Lab Pvt. Ltd, 205-210, Golden Triangle, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Rasheedunnisa Begum
- Department of Biochemistry, The Maharaja Sayajirao University of Baroda, Vadodara, 390002, Gujarat, India
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Ryan GE, Harris JE, Richmond JM. Resident Memory T Cells in Autoimmune Skin Diseases. Front Immunol 2021; 12:652191. [PMID: 34012438 PMCID: PMC8128248 DOI: 10.3389/fimmu.2021.652191] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/06/2021] [Indexed: 12/15/2022] Open
Abstract
Tissue resident memory T cells (TRM) are a critical component of the immune system, providing the body with an immediate and highly specific response against pathogens re-infecting peripheral tissues. More recently, however, it has been demonstrated that TRM cells also form during autoimmunity. TRM mediated autoimmune diseases are particularly destructive, because unlike foreign antigens, the self-antigens are never cleared, continuously activating self-reactive TRM T cells. In this article, we will focus on how TRMs mediate disease in autoimmune skin conditions, specifically vitiligo, psoriasis, cutaneous lupus erythematosus, alopecia areata and frontal fibrosing alopecia.
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Affiliation(s)
- Grace E. Ryan
- Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, United States
| | | | - Jillian M. Richmond
- Department of Dermatology, University of Massachusetts Medical School, Worcester, MA, United States
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8
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Spritz RA, Santorico SA. The Genetic Basis of Vitiligo. J Invest Dermatol 2020; 141:265-273. [PMID: 32778407 DOI: 10.1016/j.jid.2020.06.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/26/2020] [Accepted: 06/04/2020] [Indexed: 12/17/2022]
Abstract
Vitiligo is a complex disease in which autoimmune destruction of epidermal melanocytes results in patches of depigmented white skin. Vitiligo has an estimated prevalence of about 0.2-2% in different populations and approximately 0.4% in the European-derived white (EUR) population. The fraction of disease risk attributable to genetic variation, termed heritability, is high, with estimates from family studies in EUR of 0.75-0.83 and from SNP based studies estimated at 0.78. About 70% of genetic risk comes from common genetic variants and about 30% from rare genetic variants. Through candidate gene, genomewide linkage, and genomewide association studies, over 50 vitiligo susceptibility loci have been discovered. These have been combined into a vitiligo polygenic risk score, which has allowed various aspects of vitiligo genetic architecture in the EUR population to be better understood. Vitiligo has thus proved to be a particularly tractable model for investigation of complex disease genetic architecture. Here, we summarize progress to date including dissection of heritability, discovery of vitiligo susceptibility loci through candidate gene, genomewide linkage, and genomewide association studies, relationships to other autoimmune diseases, polygenic architecture of vitiligo risk, vitiligo triggering, and disease onset, and provide suggestions for future directions.
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Affiliation(s)
- Richard A Spritz
- Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
| | - Stephanie A Santorico
- Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA; Department of Mathematical and Statistical Science, University of Colorado Denver, Denver, Colorado, USA
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9
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Zhang L, Xu X, Chen S, Kang Y, Wang X, Zhang C, Xiang L. Increased Circulating CXCL10 in Non-Segmental Vitiligo Concomitant with Autoimmune Thyroid Disease and Alopecia Areata. Ann Dermatol 2019; 31:393-402. [PMID: 33911617 PMCID: PMC7992767 DOI: 10.5021/ad.2019.31.4.393] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/02/2019] [Accepted: 01/26/2019] [Indexed: 01/16/2023] Open
Abstract
Background Vitiligo is a common acquired pigmentary disease caused by destruction of epidermal melanocytes in underlying autoimmune response. Few studies have been focused on the role of chemokines in non-segmental vitiligo (NSV) concomitant with autoimmune thyroid disease (AITD) and alopecia areata (AA). Objective The aim of this study was to determine the best serum biomarker for predictive role in the progression of vitiligo and to evaluate the influence of AA and/or AITD on vitiligo by using the biomarker. Methods This prospective cohort study recruited 45 NSV patients: 14 without either AITD or AA, 12 with AITD, 11 with AA, and 8 with both AITD and AA. Serum levels of CXCL1, CXCL8, CXCL9, CXCL10, CXCL12, CXCL13, and CXCL16 were analyzed by ELISA. CXCR3 mRNA expression was detected on PBMCs by RT-PCR. Improvement was evaluated using repigmentation scales. Results Serum CXCL10 levels, along with the expression of CXCR3 mRNA were higher in NSV patients with AITD or AA alone than in those without AITD or AA. Moreover, serum CXCL10 levels, along with the expression of CXCR3 mRNA were higher in NSV patients with both AITD and AA than in those with AITD or AA alone. Poorer repigmentation was observed in NSV patients with both AA and AITD than in those with AA or AITD alone. Conclusion CXCL10 could be a biomarker to predict the progression of NSV. Dermatologists should pay much attention to those NSV patients concomitant with AITD and/or AA, for comorbidity might lead to more active autoimmune reaction.
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Affiliation(s)
- Li Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinya Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Shujun Chen
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuli Kang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiuxiu Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Chengfeng Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Leihong Xiang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
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10
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Roberts GHL, Paul S, Yorgov D, Santorico SA, Spritz RA. Family Clustering of Autoimmune Vitiligo Results Principally from Polygenic Inheritance of Common Risk Alleles. Am J Hum Genet 2019; 105:364-372. [PMID: 31327509 PMCID: PMC6698884 DOI: 10.1016/j.ajhg.2019.06.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/17/2019] [Indexed: 11/17/2022] Open
Abstract
Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are "simplex," where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some "multiplex" families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with different underlying genetic etiologies. We developed and compared the performance of several different vitiligo polygenic risk scores derived from GWAS data. By using the best-performing risk score, we find increased polygenic burden of risk alleles identified by GWAS in multiplex vitiligo cases relative to simplex cases. We additionally find evidence of polygenic transmission of common, low-effect-size risk alleles within multiplex-vitiligo-affected families. Our findings strongly suggest that family clustering of vitiligo involves a high burden of the same common, low-effect-size variants that are relevant in simplex cases. We furthermore find that a variant within the major histocompatibility complex (MHC) class II region contributes disproportionately more to risk in multiplex vitiligo cases than in simplex cases, supporting a special role for adaptive immune triggering in the etiology of multiplex cases. We suggest that genetic risk scores can be a useful tool in analyzing the genetic architecture of clinical disease subtypes and identifying subjects with unusual etiologies for further investigation.
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Affiliation(s)
- Genevieve H L Roberts
- Human Medical Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Subrata Paul
- Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO 80217, USA
| | - Daniel Yorgov
- Department of Mathematical Sciences, Purdue University Fort Wayne, Fort Wayne, IN 46805, USA
| | - Stephanie A Santorico
- Human Medical Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO 80217, USA; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, CO 80045, USA; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Richard A Spritz
- Human Medical Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
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11
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Bolívar BE, Vogel TP, Bouchier-Hayes L. Inflammatory caspase regulation: maintaining balance between inflammation and cell death in health and disease. FEBS J 2019; 286:2628-2644. [PMID: 31090171 DOI: 10.1111/febs.14926] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/09/2019] [Accepted: 05/13/2019] [Indexed: 01/15/2023]
Abstract
Members of the mammalian inflammatory caspase family, including caspase-1, caspase-4, caspase-5, caspase-11, and caspase-12, are key regulators of the innate immune response. Most studies to date have focused on the role of caspase-1 in the maturation of the proinflammatory cytokine interleukin-1β and its upstream regulation by the inflammasome signaling complexes. However, an emerging body of research has supported a role for caspase-4, caspase-5, and caspase-11 in both regulating caspase-1 activation and inducing the inflammatory form of cell death called pyroptosis. This inflammatory caspase pathway appears essential for the regulation of cytokine processing. Consequently, insight into this noncanonical pathway may reveal important and, to date, understudied targets for the treatment of autoinflammatory disorders where the inflammasome pathway is dysregulated. Here, we will discuss the mechanisms of inflammasome and inflammatory caspase activation and how these pathways intersect to promote pathogen clearance.
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Affiliation(s)
- Beatriz E Bolívar
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA
| | - Tiphanie P Vogel
- William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA.,Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Lisa Bouchier-Hayes
- Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.,William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, USA
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Baldini E, Odorisio T, Tuccilli C, Persechino S, Sorrenti S, Catania A, Pironi D, Carbotta G, Giacomelli L, Arcieri S, Vergine M, Monti M, Ulisse S. Thyroid diseases and skin autoimmunity. Rev Endocr Metab Disord 2018; 19:311-323. [PMID: 29948572 DOI: 10.1007/s11154-018-9450-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The skin is the largest organ of the body, at the boundary with the outside environment. Primarily, it provides a physical and chemical barrier against external insults, but it can act also as immune organ because it contains a whole host of immune-competent cells of both the innate and the adaptive immune systems, which cooperate in eliminating invading pathogens following tissue injury. On the other hand, improper skin immune responses lead to autoimmune skin diseases (AISD), such as pemphigus, bullous pemphigoid, vitiligo, and alopecia. Although the interplay among genetic, epigenetic, and environmental factors has been shown to play a major role in AISD etiology and progression, the molecular mechanisms underlying disease development are far from being fully elucidated. In this context, epidemiological studies aimed at defining the association of different AISD with other autoimmune pathologies revealed possible shared molecular mechanism(s) responsible for disease progression. In particular, over the last decades, a number of reports have highlighted a significant association between thyroid diseases (TD), mainly autoimmune ones (AITD), and AISD. Here, we will recapitulate the epidemiology, clinical manifestations, and pathogenesis of the main AISD, and we will summarize the epidemiological evidence showing the associations with TD as well as possible molecular mechanism(s) underlying TD and AISD pathological manifestations.
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Affiliation(s)
- Enke Baldini
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Teresa Odorisio
- Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
| | - Chiara Tuccilli
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | | | - Salvatore Sorrenti
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Antonio Catania
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Daniele Pironi
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Giovanni Carbotta
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Laura Giacomelli
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Stefano Arcieri
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Massimo Vergine
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Massimo Monti
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Salvatore Ulisse
- Department of Surgical Sciences, "Sapienza" University of Rome, Viale Regina Elena, 324, 00161, Rome, Italy.
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Aghaeii S, Amiri M, Aghaei M, Nilforoushzadeh MA. Molecular Genetics and Epidemiology of Vitiligo: A Minireview. INTERNATIONAL JOURNAL OF EPIDEMIOLOGIC RESEARCH 2018. [DOI: 10.15171/ijer.2018.22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background and aims: Vitiligo is an acquired, idiopathic, and common depigmentation disorder of the skin that affects people of all ages and both sexes equally worldwide. Although etiology of the disease is unknown, there are theories such as environment and genetic factors. Methods: In this article, we collected and summarized the appropriate manuscripts regarding the epidemiology and genetics using the terms vitiligo and genetic epidemiology in PubMed and Google Scholar. Results: Studies showed the highest prevalence of disease in African countries, but with regard to the distribution of disease in different areas, environmental factors were as important as other causes of vitiligo, and 3 genes of FOXP3, XBP1 and TSLP had the most association with the disease. Conclusion: It seems that recognition of the genetic basis of vitiligo will supply new insight into the therapies for it. Therefore, more genetic studies are needed to discover the genes and causes linked to clinical aspects of this disease.
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Affiliation(s)
- Shahrzad Aghaeii
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Masoud Amiri
- Social Determinants of Health Research Center, Shahrekord University of Medical sciences, Shahrekord, Iran
| | - Maryam Aghaei
- Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Yuan J, Sun C, Jiang S, Lu Y, Zhang Y, Gao XH, Wu Y, Chen HD. The Prevalence of Thyroid Disorders in Patients With Vitiligo: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2018; 9:803. [PMID: 30697190 PMCID: PMC6340922 DOI: 10.3389/fendo.2018.00803] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 12/20/2018] [Indexed: 11/24/2022] Open
Abstract
Background: Associations between vitiligo and thyroid disorders have been suggested, However, the prevalence of thyroid disorders in vitiligo vary widely. Purpose: To conduct a systematic review and meta-analysis assessing the prevalence of thyroid disorders in patients with vitiligo. Method: The PubMed, Cochrane Library, EMBASE, CNKI (China National Knowledge Infrastructure), Chongqing VIP database, and Wanfang database from inception to August 2, 2018 were systematically searched. The pooled prevalence and its 95% confidence interval (CI) were calculated. Results: A total of 77 eligible studies were identified and included, published from 1968 to 2018. Six thyroid disorders including subclinical hyperthyroidism, overt hyperthyroidism, subclinical hypothyroidism, overt hypothyroidism, Graves disease, and Hashimoto thyroiditis were described. The numbers of relative studies were 54 in overt hypothyroidism, 50 in overt hyperthyroidism, 25 in subclinical hypothyroidism, 19 in Hashimoto thyroiditis, 16 in Graves disease, and 10 in subclinical hyperthyroidism. The highest prevalence was 0.06 (95% CI: 0.04-0.07) in subclinical hypothyroidism, and the lowest was 0.01 in subclinical hyperthyroidism (95% CI: 0.00-0.01) or Graves disease (95% CI: 0.01-0.02). Conclusion: Six thyroid disorders showed various prevalence in vitiligo. The highest prevalence was in subclinical hypothyroidism, and the lowest was in subclinical hyperthyroidism or Graves disease. Screening vitiligo patients for thyroid disorders seem plausible, in an effort to detect potential thyroid diseases or to assess the risk of future onset.
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Abstract
Vitiligo reflects simultaneous contributions of multiple genetic risk factors and environmental triggers. Genomewide association studies have discovered approximately 50 genetic loci contributing to vitiligo risk. At many vitiligo susceptibility loci, the relevant genes and DNA sequence variants are identified. Many encode proteins involved in immune regulation, several play roles in cellular apoptosis, and others regulate functions of melanocytes. Although many of the specific biologic mechanisms need elucidation, it is clear that vitiligo is an autoimmune disease involving a complex relationship between immune system programming and function, aspects of the melanocyte autoimmune target, and dysregulation of the immune response.
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Affiliation(s)
- Richard A Spritz
- Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, 12800 East 19th Avenue, Room 3100, MS8300, Aurora, CO 80045, USA.
| | - Genevieve H L Andersen
- Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, 12800 East 19th Avenue, Room 3100, MS8300, Aurora, CO 80045, USA
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Dey-Rao R, Sinha AA. Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets. BMC Genomics 2017; 18:109. [PMID: 28129744 PMCID: PMC5273810 DOI: 10.1186/s12864-017-3510-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 01/19/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. METHODS We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. RESULTS Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. CONCLUSIONS We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional "hot spots" observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.
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Affiliation(s)
- Rama Dey-Rao
- Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 6078 Clinical and Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14203, USA
| | - Animesh A Sinha
- Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 6078 Clinical and Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14203, USA.
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Baldini E, Odorisio T, Sorrenti S, Catania A, Tartaglia F, Carbotta G, Pironi D, Rendina R, D’Armiento E, Persechino S, Ulisse S. Vitiligo and Autoimmune Thyroid Disorders. Front Endocrinol (Lausanne) 2017; 8:290. [PMID: 29163360 PMCID: PMC5663726 DOI: 10.3389/fendo.2017.00290] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 10/11/2017] [Indexed: 12/12/2022] Open
Abstract
Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5-1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves' disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s).
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Affiliation(s)
- Enke Baldini
- Department of Surgical Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Teresa Odorisio
- Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy
| | - Salvatore Sorrenti
- Department of Surgical Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Antonio Catania
- Department of Surgical Sciences, “Sapienza” University of Rome, Rome, Italy
| | | | - Giovanni Carbotta
- Department of Surgical Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Daniele Pironi
- Department of Surgical Sciences, “Sapienza” University of Rome, Rome, Italy
| | - Roberta Rendina
- Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Rome, Italy
| | - Eleonora D’Armiento
- Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Rome, Italy
| | | | - Salvatore Ulisse
- Department of Surgical Sciences, “Sapienza” University of Rome, Rome, Italy
- *Correspondence: Salvatore Ulisse,
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18
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Thomas KS, Batchelor JM, Bath-Hextall F, Chalmers JR, Clarke T, Crowe S, Delamere FM, Eleftheriadou V, Evans N, Firkins L, Greenlaw N, Lansbury L, Lawton S, Layfield C, Leonardi-Bee J, Mason J, Mitchell E, Nankervis H, Norrie J, Nunn A, Ormerod AD, Patel R, Perkins W, Ravenscroft JC, Schmitt J, Simpson E, Whitton ME, Williams HC. A programme of research to set priorities and reduce uncertainties for the prevention and treatment of skin disease. PROGRAMME GRANTS FOR APPLIED RESEARCH 2016. [DOI: 10.3310/pgfar04180] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BackgroundSkin diseases are very common and can have a large impact on the quality of life of patients and caregivers. This programme addressed four diseases: (1) eczema, (2) vitiligo, (3) squamous cell skin cancer (SCC) and (4) pyoderma gangrenosum (PG).ObjectiveTo set priorities and reduce uncertainties for the treatment and prevention of skin disease in our four chosen diseases.DesignMixed methods including eight systematic reviews, three prioritisation exercises, two pilot randomised controlled trials (RCTs), three feasibility studies, two core outcome initiatives, four funding proposals for national RCTs and one completed national RCT.SettingSecondary care, primary care and the general population.ParticipantsPatients (and their caregivers) with eczema, vitiligo, SCC and PG, plus health-care professionals with an interest in skin disease.InterventionsOur three intervention studies included (1) barrier enhancement using emollients from birth to prevent eczema (pilot RCT); (2) handheld narrowband ultraviolet light B therapy for treating vitiligo (pilot RCT); and (3) oral ciclosporin (Neoral®, Novartis Pharmaceuticals) compared with oral prednisolone for managing PG (pragmatic national RCT).ResultsSystematic reviews included two overarching systematic reviews of RCTs of treatments for eczema and vitiligo, an umbrella review of systematic reviews of interventions for the prevention of eczema, two reviews of treatments for SCC (one included RCTs and the second included observational studies), and three reviews of outcome measures and outcome reporting. Three prioritisation partnership exercises identified 26 priority areas for future research in eczema, vitiligo and SCC. Two international consensus initiatives identified four core domains for future eczema trials and seven core domains for vitiligo trials. Two pilot RCTs and three feasibility studies critically informed development of four trial proposals for external funding, three of which are now funded and one is pending consideration by funders. Our pragmatic RCT tested the two commonly used systemic treatments for PG (prednisolone vs. ciclosporin) and found no difference in their clinical effectiveness or cost-effectiveness. Both drugs showed limited benefit. Only half of the participants’ ulcers had healed by 6 months. For those with healed ulcers, recurrence was common (30%). Different side effect profiles were noted for each drug, which can inform clinical decisions on an individual patient basis. Three researchers were trained to PhD level and a dermatology patient panel was established to ensure patient involvement in all aspects of the programme.ConclusionsFindings from this programme of work have already informed clinical guidelines and patient information resources. Feasibility studies have ensured that large national pragmatic trials will now be conducted on important areas of treatment uncertainty that address the needs of patients and the NHS. There is scope for considerable improvement in terms of trial design, conduct and reporting for RCTs of skin disease, which can be improved through wider collaboration, registration of trial protocols and complete reporting and international consensus over core outcome sets. Three national trials have now been funded as a result of this work. Two international initiatives to establish how best to measure the core outcome domains for eczema and vitiligo are ongoing.Trial registrationCurrent Controlled Trials Barrier Enhancement for Eczema Prevention (BEEP) (ISRCTN84854178 and NCT01142999), Study of Treatments fOr Pyoderma GAngrenosum Patients (STOP GAP) (ISRCTN35898459) and Hand Held NB-UVB for Early or Focal Vitiligo at Home (HI-Light Pilot Trial) (NCT01478945).FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 4, No. 18. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Kim S Thomas
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | | | | | - Joanne R Chalmers
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | - Tessa Clarke
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | | | - Finola M Delamere
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | | | - Nicholas Evans
- Trust Headquarters, West Hertfordshire Hospital NHS Trust, Hemel Hempstead, UK
| | - Lester Firkins
- Strategy and Development Group, James Lind Alliance, Oxford, UK
| | - Nicola Greenlaw
- Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
| | - Louise Lansbury
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | - Sandra Lawton
- Dermatology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Carron Layfield
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | - Jo Leonardi-Bee
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK
| | - James Mason
- School of Medicine, Pharmacy and Health, Durham University, Durham, UK
| | - Eleanor Mitchell
- Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, UK
| | - Helen Nankervis
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | - John Norrie
- Health Services Research Unit, University of Aberdeen, Aberdeen, UK
| | - Andrew Nunn
- Medical Research Council (MRC) Clinical Trials Unit, University College London, London, UK
| | | | - Ramesh Patel
- Radcliffe-on-Trent Health Centre, Nottingham, UK
| | - William Perkins
- Dermatology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jane C Ravenscroft
- Dermatology Department, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jochen Schmitt
- Centre for Evidence-based Healthcare, Medical Faculty Carl Gustav Carus, Dresden, Germany
| | - Eric Simpson
- Oregon Health and Science University, Portland, OR, USA
| | - Maxine E Whitton
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
| | - Hywel C Williams
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK
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Shen C, Gao J, Sheng Y, Dou J, Zhou F, Zheng X, Ko R, Tang X, Zhu C, Yin X, Sun L, Cui Y, Zhang X. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci. Front Genet 2016; 7:3. [PMID: 26870082 PMCID: PMC4740779 DOI: 10.3389/fgene.2016.00003] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/11/2016] [Indexed: 01/15/2023] Open
Abstract
Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo.
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Affiliation(s)
- Changbing Shen
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Jing Gao
- Department of Dermatology, The Second Affiliated Hospital, Anhui Medical University Hefei, China
| | - Yujun Sheng
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Jinfa Dou
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Fusheng Zhou
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Xiaodong Zheng
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Randy Ko
- Department of Biochemistry, University of New Mexico Albuquerque, NM, USA
| | - Xianfa Tang
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Caihong Zhu
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Xianyong Yin
- Department of Genetics and Renaissance Computing Institute, University of North Carolina at Chapel Hill Chapel Hill, NC, USA
| | - Liangdan Sun
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical University Hefei, China
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital Beijing, China
| | - Xuejun Zhang
- Institute and Department of Dermatology, The First Affiliated Hospital, Anhui Medical UniversityHefei, China; Department of Dermatology, The Second Affiliated Hospital, Anhui Medical UniversityHefei, China
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The coexistence of peripheral nerve sheath tumors and vitiligo: more than coincidence? Acta Neurochir (Wien) 2016; 158:95-9; discussion 99. [PMID: 26607956 DOI: 10.1007/s00701-015-2629-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 10/28/2015] [Indexed: 10/22/2022]
Abstract
Neurocristopathies arise from abnormal migration, differentiation, or proliferation of neural crest derivatives, leading to diverse clinical and pathological features. They are classified into dysgenetic or neoplastic, and can affect single or multiple sites (simple versus complex). Examples include congenital melanocytic nevi, neuroblastoma, Hirshsprung's disease, Waardenburg's syndrome, neurofibromatosis (NF) 1 and multiple endocrine neoplasia (MEN) 2A and 2B. We report two cases of peripheral nerve sheath tumors associated with vitiligo and discuss the possible implicated embryologic, genetic and molecular mechanisms. To our knowledge, we also report the first case of de novo malignant peripheral nerve sheath tumor (MPNST) associated with vitiligo.
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21
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Dey-Rao R, Sinha AA. Interactome analysis of gene expression profile reveals potential novel key transcriptional regulators of skin pathology in vitiligo. Genes Immun 2015; 17:30-45. [DOI: 10.1038/gene.2015.48] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 09/25/2015] [Accepted: 09/29/2015] [Indexed: 12/13/2022]
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22
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Schunter JA, Löffler D, Wiesner T, Kovacs P, Badenhoop K, Aust G, Tönjes A, Müller P, Baber R, Simon JC, Führer D, Pfäffle RW, Thiery J, Stumvoll M, Kiess W, Kratzsch J, Körner A. A novel FoxD3 Variant Is Associated With Vitiligo and Elevated Thyroid Auto-Antibodies. J Clin Endocrinol Metab 2015; 100:E1335-42. [PMID: 26267147 DOI: 10.1210/jc.2015-2126] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Vitiligo frequently coincides with autoimmune endocrinopathies, particularly Hashimoto's thyroiditis (HT). Genetic susceptibility may underlie this coincident occurrence. One candidate region is the autoimmunity susceptibility locus on chromosome 1, which encompasses forkhead transcription factor D3 (FoxD3), a gene involved in embryonal melanogenesis. We identified a promotor variant (rs78645479) in an index case of vitiligo + HT + candidiasis and evaluated its clinical and functional relevance. DESIGN We genotyped 281 patients with variable autoimmune endocrinopathies: HT, Graves' disease (GD), type 1 diabetes (T1D), Addison's disease (AD), autoimmune polyglandular syndrome (APS), and/or vitiligo and 1858 controls. Furthermore, we experimentally assessed the effect of the variant on promotor activity and assessed the expression of FoxD3 in human thyroid tissue samples. RESULTS Patients with vitiligo had a higher frequency of the risk allele (30%) compared with healthy controls (18.2%). In addition, the variant was associated with the incidence of elevated anti-TPO antibodies and anti-Tg antibodies, but not with TSH, FT3, or FT4 levels and also not with GD, T1D, AD, or APS. Functionally, the variant increased transcriptional activity in Jurkat and in Hek293 cells. We confirmed gene expression of FoxD3 in human thyroid tissue, which seemed elevated in thyroid tissue samples of some patients with GD and nonautoimmune goiter but not in patients with HT. CONCLUSION In addition to a possible association of rs78645479 in FoxD3 with vitiligo, our data on the association of this FoxD3 variant with thyroid autoantibodies suggest a potential involvement of FoxD3 in thyroid immunoregulation.
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Affiliation(s)
- Jo Ana Schunter
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Dennis Löffler
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Tobias Wiesner
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Peter Kovacs
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Klaus Badenhoop
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Gabriela Aust
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Anke Tönjes
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Peter Müller
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Ronny Baber
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Jan C Simon
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Dagmar Führer
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Roland W Pfäffle
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Joachim Thiery
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Michael Stumvoll
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Wieland Kiess
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Jürgen Kratzsch
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
| | - Antje Körner
- Center for Paediatric Research Leipzig (J.A.S., D.L., R.W.P., W.K., A.K.), University Hospital for Children & Adolescents, 04103 Leipzig, Germany; Ambulatory Health Care Center Metabolic Medicine (T.W., P.M.), 04103 Leipzig, Germany; Integrated Research and Treatment Center (P.K., M.S., A.K.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine 1, Division of Endocrinology & Metabolism (K.B.), Goethe-University Hospital, 60590 Frankfurt, Germany; Department of Surgery, Research Laboratories and Clinic of Visceral, Transplantation, Thoracic, and Vascular Surgery (G.A.), University of Leipzig, 04103 Leipzig, Germany; Deptartment of Medicine, Division of Endocrinology and Nephrology (A.T., D.F., M.S.), University of Leipzig, 04103 Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics (R.B., J.T., J.K.), University Hospital Leipzig, 04103 Leipzig, Germany; and Department of Dermatology, Venereology, and Allergology (J.C.S.), University of Leipzig, 04103 Leipzig Germany
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Matin R. Vitiligo in adults and children: surgical interventions. BMJ CLINICAL EVIDENCE 2015; 2015:1717. [PMID: 25800413 PMCID: PMC4371616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
INTRODUCTION Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, due to the loss of functioning melanocytes. The extent and distribution of vitiligo often changes during the course of a person's lifetime and its progression is unpredictable. METHODS AND OUTCOMES We conducted a systematic review and aimed to answer the following clinical question: What are the effects of surgical interventions for vitiligo in adults and in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS We found four studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS In this systematic review we present information relating to the effectiveness and safety of the following interventions: blister grafts, cultured cellular transplantation, non-cultured cellular transplantation, punch/mini grafts, and split thickness skin grafts.
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Mohammed GF, Gomaa AHA, Al-Dhubaibi MS. Highlights in pathogenesis of vitiligo. World J Clin Cases 2015; 3:221-30. [PMID: 25789295 PMCID: PMC4360494 DOI: 10.12998/wjcc.v3.i3.221] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 12/27/2014] [Accepted: 01/09/2015] [Indexed: 02/05/2023] Open
Abstract
Vitiligo is a common pigmentary disorder. Many studies across decades and all over the world have attempted to illustrate the pathogenesis behind it; however, the pathogenesis of vitiligo remains elusive. This review article, we present the findings behind the most and updated theories behind this psychologically debilitating and disfiguring disease. The discussion begun with the role of genetic predisposition followed by neural theory first proposed in the 1950s. We highlight the autoimmune hypothesis, followed by the reactive oxygen species model, zinc-α2-glycoprotein deficiency hypothesis, viral theory, intrinsic theory and biochemical, molecular and cellular alterations accounting for loss of functioning melanocytes in vitiligo. Many theories were elaborated to clarify vitiligo pathogenesis. It is a multifactorial disease involving the interplay of several factors. Future research is needed to clarify the interaction of these factors for better understanding of vitiligo pathogenesis and subsequent successful treatment.
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Transporter TAP1-637G and immunoproteasome PSMB9-60H variants influence the risk of developing vitiligo in the Saudi population. DISEASE MARKERS 2014. [PMID: 25548428 DOI: 10.1155/2014/260732]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We evaluated whether TAP1-rs1135216 (p.637D>G) and PSMB9-rs17587 (p.60R>H) were significantly associated with the risk and severity of vitiligo among Saudi patients. One hundred seventy-two subjects were genotyped for the TAP1-rs1135216 and PSMB9-rs17587 variants using endonuclease digestions of amplified genomic DNA. The TAP1-rs1135216 and PSMB9-rs17587 mutant alleles were strongly associated with vitiligo, with odds ratios showing five fold and two fold risks (P < 0.0001 and P = 0.007, resp.). In TAP1-rs1135216, the 637G mutant allele was more frequent in cases (74%) than in healthy controls. In cases, the 60H mutant allele PSMB9-rs17587 was less frequent (42%) than the wild-type 60R allele (58%). Vitiligo vulgaris was the most common type of disease, associated with the DG (55%) and GG (46%) genotypes for rs1135216 and with the RH genotype (59%) for rs17587. The heterozygous 637DG and 60RH genotypes were each linked with active phenotypes in 64% of cases. In conclusion, the TAP1-rs1135216 and PSMB9-rs17587 variants are significantly associated with vitiligo, and even one copy of these mutant alleles can influence the risk among Saudis. Vitiligo vulgaris is associated with genotypes containing the mutant G and H alleles.
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26
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Elhawary NA, Bogari N, Jiffri EH, Rashad M, Fatani A, Tayeb M. Transporter TAP1-637G and immunoproteasome PSMB9-60H variants influence the risk of developing vitiligo in the Saudi population. DISEASE MARKERS 2014; 2014:260732. [PMID: 25548428 PMCID: PMC4273470 DOI: 10.1155/2014/260732] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 11/20/2014] [Accepted: 11/21/2014] [Indexed: 02/08/2023]
Abstract
We evaluated whether TAP1-rs1135216 (p.637D>G) and PSMB9-rs17587 (p.60R>H) were significantly associated with the risk and severity of vitiligo among Saudi patients. One hundred seventy-two subjects were genotyped for the TAP1-rs1135216 and PSMB9-rs17587 variants using endonuclease digestions of amplified genomic DNA. The TAP1-rs1135216 and PSMB9-rs17587 mutant alleles were strongly associated with vitiligo, with odds ratios showing five fold and two fold risks (P < 0.0001 and P = 0.007, resp.). In TAP1-rs1135216, the 637G mutant allele was more frequent in cases (74%) than in healthy controls. In cases, the 60H mutant allele PSMB9-rs17587 was less frequent (42%) than the wild-type 60R allele (58%). Vitiligo vulgaris was the most common type of disease, associated with the DG (55%) and GG (46%) genotypes for rs1135216 and with the RH genotype (59%) for rs17587. The heterozygous 637DG and 60RH genotypes were each linked with active phenotypes in 64% of cases. In conclusion, the TAP1-rs1135216 and PSMB9-rs17587 variants are significantly associated with vitiligo, and even one copy of these mutant alleles can influence the risk among Saudis. Vitiligo vulgaris is associated with genotypes containing the mutant G and H alleles.
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Affiliation(s)
- Nasser Attia Elhawary
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 57543, Mecca 21955, Saudi Arabia
- Department of Molecular Genetics, Medical Genetics Center, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Neda Bogari
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 57543, Mecca 21955, Saudi Arabia
| | - Essam Hussien Jiffri
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mona Rashad
- Department of Pediatrics, Al-Qatif Central Hospital, Dammam 31911, Saudi Arabia
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Abdulhamid Fatani
- National Guard Hospitals, Faculty of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11564, Saudi Arabia
| | - Mohammed Tayeb
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O. Box 57543, Mecca 21955, Saudi Arabia
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Tarlé RG, Nascimento LMD, Mira MT, Castro CCSD. Vitiligo--part 1. An Bras Dermatol 2014; 89:461-70. [PMID: 24937821 PMCID: PMC4056705 DOI: 10.1590/abd1806-4841.20142573] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/25/2013] [Indexed: 12/27/2022] Open
Abstract
Vitiligo is a chronic stigmatizing disease, already known for millennia, which
mainly affects melanocytes from epidermis basal layer, leading to the
development of hypochromic and achromic patches. Its estimated prevalence is
0.5% worldwide. The involvement of genetic factors controlling susceptibility to
vitiligo has been studied over the last decades, and results of previous studies
present vitiligo as a complex, multifactorial and polygenic disease. In this
context, a few genes, including DDR1, XBP1 and NLRP1 have been
consistently and functionally associated with the disease. Notwithstanding,
environmental factors that precipitate or maintain the disease are yet to be
described. The pathogenesis of vitiligo has not been totally clarified until now
and many theories have been proposed. Of these, the autoimmune hypothesis is now
the most cited and studied among experts. Dysfunction in metabolic pathways,
which could lead to production of toxic metabolites causing damage to
melanocytes, has also been investigated. Melanocytes adhesion deficit in
patients with vitiligo is mainly speculated by the appearance of Köebner
phenomenon, recently, new genes and proteins involved in this deficit have been
found.
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Current aspects of vitiligo genetics. Postepy Dermatol Alergol 2014; 31:247-55. [PMID: 25254010 PMCID: PMC4171675 DOI: 10.5114/pdia.2014.43497] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 05/17/2014] [Accepted: 05/27/2014] [Indexed: 12/24/2022] Open
Abstract
Vitiligo is a common acquired depigmentation disorder of the skin manifested by the presence of white macules. The disease occurs at a frequency of approximately 1–4% of the world population. Currently, the most popular theory of vitiligo development is a multifactorial hypothesis according to which genetic conditions predispose vitiligo macules to occur as a result of specific environmental factors. According to the genetic hypothesis, vitiligo inheritance is multigenic. Genetic studies conducted so far concern patients with non-segmental vitiligo. There are three basic techniques of genetic studies: candidate gene association studies, genomewide linkage studies and genome-wide association studies (GWAS). The GWAS are the “gold standard” for detecting susceptibility genes. Up to now, approximately 36 convincing non-segmental vitiligo susceptibility loci have been identified. Approximately 90% of them encode immunoregulatory proteins, while approximately 10% encode melanocyte proteins. The existence of various associations between vitiligo and other autoimmune diseases may provide new knowledge on the causes of many disorders. Examples include the inverse relationship between vitiligo and melanoma and association of vitiligo with other autoimmune diseases. The main goal of all researches is to find new, optimal therapeutic strategies for vitiligo and other autoimmune diseases.
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Gingival vitiligo: report of a case and review of the literature. Case Rep Dent 2014; 2014:874025. [PMID: 25013731 PMCID: PMC4074980 DOI: 10.1155/2014/874025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Accepted: 05/21/2014] [Indexed: 11/17/2022] Open
Abstract
Rarely cases have been reported regarding depigmented lesions of the oral cavity. On reviewing the literature, only few cases of gingival vitiligo or similar lesions have been reported till date. These lesions pose a cosmetic challenge. We present here a case of vitiligo affecting gingiva. Vitiligo has been defined as an acquired, slowly progressive loss of cutaneous pigment which occurs as irregular, sharply defined patches which may or may not be surrounded by macroscopic hyperpigmentation. Differential diagnosis, detailed clinical history, histopathology, immunohistochemistry, and pathogenesis of this condition are discussed.
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Spritz RA. Modern vitiligo genetics sheds new light on an ancient disease. J Dermatol 2014; 40:310-8. [PMID: 23668538 DOI: 10.1111/1346-8138.12147] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 02/20/2013] [Indexed: 01/08/2023]
Abstract
Vitiligo is a complex disorder in which autoimmune destruction of melanocytes results in white patches of skin and overlying hair. Over the past several years, extensive genetic studies have outlined a biological framework of vitiligo pathobiology that underscores its relationship to other autoimmune diseases. This biological framework offers insight into both vitiligo pathogenesis and perhaps avenues towards more effective approaches to treatment and even disease prevention.
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Affiliation(s)
- Richard A Spritz
- Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
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Pothlichet J, Quintana-Murci L. The genetics of innate immunity sensors and human disease. Int Rev Immunol 2013; 32:157-208. [PMID: 23570315 DOI: 10.3109/08830185.2013.777064] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Since their discovery, innate immunity microbial sensors have been increasingly studied and shown to play a critical role in innate responses to microbes in several experimental in vitro, ex vivo, and animal models. However, their role in the human response to infection in natural conditions has just started to be deciphered, by means of clinical studies of primary immunodeficiencies and epidemiological genetic studies. Here, we summarize the major findings concerning the genetic diversity of the various families of microbial sensors in humans, and of other molecules involved in the signaling pathways they trigger. Specifically, we review the genetic associations, revealed by both clinical and epidemiological genetics studies, of microbial sensors from five different families: Toll-like receptors, C-type lectin receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. In particular, we consider the relationships between variation at the genes encoding these molecules and susceptibility to and the severity of infectious diseases and other clinical conditions associated with immune dysfunction, including autoimmunity, inflammation, allergy, and cancer. Despite the fact that the genetic links between innate immunity sensors and human disorders remain still limited, human genetics studies are increasingly improving our understanding of the genuine functions of microbial sensors and downstream signaling molecules in the natural setting.
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Affiliation(s)
- Julien Pothlichet
- Institut Pasteur, Unit of Human Evolutionary Genetics, Paris, France
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Abstract
BACKGROUND Vitiligo is a commonly encountered pigmentary disorder. Numerous studies and investigations from all over the world have attempted to determine the mechanisms behind this disease; however, the pathogenesis of vitiligo remains elusive. OBJECTIVE n this comprehensive review article, we present the findings behind the five overarching theories of what causes this disfiguring and psychologically debilitating disease. METHOD We begin our discussion with the role of genetic predisposition and move onward to the neural theory first proposed in the 1950s. Next we discuss the autoimmune hypothesis, followed by the reactive oxygen species model, and conclude by describing the findings of the more recent melanocytorrhagy hypothesis. CONCLUSION Although the exact pathogenesis of vitiligo is uncertain, each of these theories likely plays a role. Understanding each theory would pave the way for therapeutic advances for this disease.
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Affiliation(s)
- Neel Malhotra
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Hercogová J, Schwartz RA, Lotti TM. Classification of vitiligo: a challenging endeavor. Dermatol Ther 2012; 25 Suppl 1:S10-6. [DOI: 10.1111/dth.12010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Jana Hercogová
- Department of Dermatology and Venereology; 2nd Medical School; Charles University of Prague; Prague; Czech Republic
| | - Robert A. Schwartz
- Dermatology and Pathology; New Jersey Medical School; Newark; New Jersey
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Yu R, Broady R, Huang Y, Wang Y, Yu J, Gao M, Levings M, Wei S, Zhang S, Xu A, Su M, Dutz J, Zhang X, Zhou Y. Transcriptome analysis reveals markers of aberrantly activated innate immunity in vitiligo lesional and non-lesional skin. PLoS One 2012; 7:e51040. [PMID: 23251420 PMCID: PMC3519491 DOI: 10.1371/journal.pone.0051040] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 10/31/2012] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Vitiligo is characterized by the death of melanocytes in the skin. This is associated with the presence of T cell infiltrates in the lesional borders. However, at present, there is no detailed and systematic characterization on whether additional cellular or molecular changes are present inside vitiligo lesions. Further, it is unknown if the normal appearing non-lesional skin of vitiligo patients is in fact normal. The purpose of this study is to systematically characterize the molecular and cellular characteristics of the lesional and non-lesional skin of vitiligo patients. METHODS AND MATERIALS Paired lesional and non-lesional skin biopsies from twenty-three vitiligo patients and normal skin biopsies from sixteen healthy volunteers were obtained with informed consent. The following aspects were analyzed: (1) transcriptome changes present in vitiligo skin using DNA microarrays and qRT-PCR; (2) abnormal cellular infiltrates in vitiligo skin explant cultures using flow cytometry; and (3) distribution of the abnormal cellular infiltrates in vitiligo skin using immunofluorescence microscopy. RESULTS Compared with normal skin, vitiligo lesional skin contained 17 genes (mostly melanocyte-specific genes) whose expression was decreased or absent. In contrast, the relative expression of 13 genes was up-regulated. The up-regulated genes point to aberrant activity of the innate immune system, especially natural killer cells in vitiligo. Strikingly, the markers of heightened innate immune responses were also found to be up-regulated in the non-lesional skin of vitiligo patients. CONCLUSIONS AND CLINICAL IMPLICATIONS As the first systematic transcriptome characterization of the skin in vitiligo patients, this study revealed previously unknown molecular markers that strongly suggest aberrant innate immune activation in the microenvironment of vitiligo skin. Since these changes involve both lesional and non-lesional skin, our results suggest that therapies targeting the entire skin surface may improve treatment outcomes. Finally, this study revealed novel mediators that may facilitate future development of vitiligo therapies.
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Affiliation(s)
- Richard Yu
- Institute of Dermatology, Anhui Medical University, Hefei, China
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
| | - Raewyn Broady
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | - Yuanshen Huang
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
| | - Yang Wang
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
| | - Jie Yu
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
| | - Min Gao
- Institute of Dermatology, Anhui Medical University, Hefei, China
| | - Megan Levings
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
| | - Shencai Wei
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
| | - Shengquan Zhang
- Institute of Dermatology, Anhui Medical University, Hefei, China
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
| | - Aie Xu
- Department of Dermatology, The Third People's Hospital, Hangzhou, China
| | - Mingwan Su
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
| | - Jan Dutz
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
- Skin Tumor Group, British Columbia Cancer Agency, Vancouver, Canada
| | - Xuejun Zhang
- Institute of Dermatology, Anhui Medical University, Hefei, China
| | - Youwen Zhou
- Institute of Dermatology, Anhui Medical University, Hefei, China
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada
- Skin Tumor Group, British Columbia Cancer Agency, Vancouver, Canada
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35
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Zhang X. Genome-wide association study of skin complex diseases. J Dermatol Sci 2012; 66:89-97. [PMID: 22480995 DOI: 10.1016/j.jdermsci.2012.02.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 02/24/2012] [Indexed: 01/04/2023]
Abstract
Complex diseases are caused by both genetic and environmental factors. Over decades, scientists endeavored to uncover the genetic myth of complex diseases by linkage and association studies. Since 2005, the genome-wide association study (GWAS) has been proved to be the most powerful and efficient study design thus far in identifying genetic variants that are associated with complex diseases. More than 230 complex diseases and traits have been investigated by this approach. In dermatology, 10 skin complex diseases have been investigated, a wealth of common susceptibility variants conferring risk for skin complex diseases have been discovered. These findings point to genes and/or loci involved in biological systems worth further investigating by using other methodologies. Certainly, as our understanding of the genetic etiology of skin complex diseases continues to mature, important opportunities will emerge for developing more effective diagnostic and clinical management tools for these diseases.
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Affiliation(s)
- Xuejun Zhang
- Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University, Hefei, Anhui, China.
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Spritz RA. Six decades of vitiligo genetics: genome-wide studies provide insights into autoimmune pathogenesis. J Invest Dermatol 2012; 132:268-73. [PMID: 21993561 PMCID: PMC3258303 DOI: 10.1038/jid.2011.321] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Generalized vitiligo (GV) is a complex disease in which patchy depigmentation results from autoimmune loss of melanocytes from affected regions. Genetic analyses of GV span six decades, with the goal of understanding biological mechanisms and elucidating pathways that underlie the disease. The earliest studies attempted to describe the mode of inheritance and genetic epidemiology. Early genetic association studies of biological candidate genes resulted in some successes, principally HLA and PTPN22, but in hindsight many such reports now seem to be false-positives. Later, genome-wide linkage studies of multiplex GV families identified NLRP1 and XBP1, which appear to be valid GV susceptibility genes that control key aspects of immune regulation. Recently, the application of genome-wide association studies to analysis of GV has produced a rich yield of validated GV susceptibility genes that encode components of biological pathways reaching from immune cells to the melanocyte. These genes and pathways provide insights into underlying pathogenetic mechanisms and possible triggers of GV, establish relationships to other autoimmune diseases, and may provide clues to potential new approaches to GV treatment and perhaps even prevention. These results thus validate the hopes and efforts of the early investigators who first attempted to comprehend the genetic basis of vitiligo.
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Affiliation(s)
- Richard A Spritz
- Human Medical Genetics Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
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Poojary S. Vitiligo and associated autoimmune disorders: a retrospective hospital-based study in Mumbai, India. Allergol Immunopathol (Madr) 2011; 39:356-61. [PMID: 21474231 DOI: 10.1016/j.aller.2010.12.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2010] [Revised: 11/30/2010] [Accepted: 12/07/2010] [Indexed: 11/25/2022]
Abstract
BACKGROUND It is a hospital based study focusing on epidemiological aspects of vitiligo and association with autoimmune disorders. There are few studies elucidating the association of autoimmune disorders with vitiligo in the Indian population. Our study is a small attempt in this direction. AIM To study epidemiological parameters of vitiligo and to study coexistence of autoimmune disorders. MATERIALS AND METHODS Records of 33,252 new patients attending the dermatology outpatient department from June 2002 to June 2008 were analysed for the presence of vitiligo and details of important epidemiological variables, and associated autoimmune disorders of these patients were collected and analysed. RESULTS Total number of vitiligo patients was 204. Proportion of vitiligo patients was 0.61%. Male:female proportion was almost equal. Family history of vitiligo was seen in 3.43% of cases. Associated autoimmune disorders were seen in 2.94% cases and were mainly skin associated autoimmune diseases (morphoea, alopecia areata, discoid lupus erythematosus, and pemphigus erythematosus) except for one case of Grave's disease. CONCLUSION Association of vitiligo with other autoimmune diseases emphasizes autoimmune aetiology of vitiligo. This study also emphasizes the need to actively look for, and if necessary, investigate patients with vitiligo for other autoimmune diseases.
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A pattern of association between clinical form of vitiligo and disease-related variables in a Brazilian population. J Dermatol Sci 2011; 65:63-7. [PMID: 22030153 DOI: 10.1016/j.jdermsci.2011.09.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2011] [Revised: 07/26/2011] [Accepted: 09/25/2011] [Indexed: 11/20/2022]
Abstract
BACKGROUND Vitiligo classification systems are often based exclusively on the number and distribution of the white patches. To what extend these classification protocols reflect possible different pathophysiological basis for vitiligo or carry any prognostic value is currently unknown. OBJECTIVE To investigate patterns of association between type of vitiligo and common disease-related variables, in order to advance on the understanding of the exact nature of different clinical forms of disease, as well as to identify features with prognostic value for clinical progression of early diagnosed vitiligo. MATERIALS AND METHODS This is a cross-sectional study of a population sample from south of Brazil composed of 586 independent vitiligo-affected individuals. Different strategies of case-control analysis were employed to test for association between the three most common vitiligo clinical types and age of onset, family history of vitiligo, occurrence of Köebner phenomenon (KP) and presence of autoimmune co-morbidity. RESULTS Individuals affected by segmental vitiligo showed lower average age of onset (16 years) when compared with vulgaris (23.9 years) and acrofacial cases (29 years) (p<0.001). The distribution of occurrence of KP, family history of vitiligo and co-occurrence of autoimmune disease followed a gradient pattern, with high, intermediate and low chance of occurrence of all three variables observed for vulgaris, acrofacial and segmental vitiligo, respectively (p<0.001 for overall distribution). CONCLUSION Results indicate a uniform pattern of association between vitiligo clinical forms and KP, positive vitiligo family history and occurrence of co-morbidity autoimmune. The impact of the observed pattern of association over disease prognosis and classification is discussed.
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Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: A comprehensive overview. J Am Acad Dermatol 2011; 65:473-491. [DOI: 10.1016/j.jaad.2010.11.061] [Citation(s) in RCA: 384] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Revised: 10/23/2010] [Accepted: 11/05/2010] [Indexed: 12/20/2022]
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Al-Shobaili HA. Update on the genetics characterization of vitiligo. Int J Health Sci (Qassim) 2011; 5:167-79. [PMID: 23267294 PMCID: PMC3521835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023] Open
Abstract
Vitiligo is an autoimmune skin disorder in which autoimmune-mediated destruction of melanocytes caused depigmentation of skin patches. The complex genetics of vitiligo involves multiple susceptibility loci, genetic heterogeneity and incomplete penetrance with gene-gene and gene-environment interactions. In order to clarify the genetic factors, two different principal approaches have applied for the identification of genomic regions or candidate genes that mediate susceptibility to vitiligo. First approach is the genome-wide linkage analyses, which is conducted by scanning of entire human genome for genomic regions that are linked to the development of vitiligo. The other approach is functional candidate gene association (FCGA) analyses that detect specific candidate genes, which are expected to involve in disease on the basis of their priori biological functions. Genomic-wide scans have provided a strong support for vitiligo susceptibility genes on chromosomes 4q13-q21, 1p31, 7q22, 8p12 and 17p13, while loci of interest at 6p, 6q, 14q, 9q, 13q, 19p and 22q required further follow-up. Whereas, FCGA studies have identified some candidate genes which are associated with vitiligo, such as HLA, AIRE, VIT1, CAT, FOXD3, ESR1, COMT, PTPN22, NALP1, PDGFRA, MYG1, MITF, CD117, XBP1, FAS, COX2, EDN1 and ACE, but few of them reports now appear to be false-positive. This review will provides an update on genetics of vitiligo based on the identification of novel candidate genes that represent, in my opinion as optimal utility for future therapeutic targets in the pathogenesis of vitiligo.
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Affiliation(s)
- Hani A. Al-Shobaili
- Department of Dermatology, College of Medicine, Qassim University, Saudi Arabia
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Recent progress in the genetics of generalized vitiligo. J Genet Genomics 2011; 38:271-8. [PMID: 21777851 DOI: 10.1016/j.jgg.2011.05.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Revised: 05/18/2011] [Accepted: 05/23/2011] [Indexed: 11/23/2022]
Abstract
Vitiligo is an acquired disease characterized principally by patchy depigmentation of skin and overlying hair. Generalized vitiligo (GV), the predominant form of the disorder, results from autoimmune loss of melanocytes from affected regions. GV is a "complex trait", inherited in a non-Mendelian polygenic, multifactorial manner. GV is epidemiologically associated with other autoimmune diseases, both in GV patients and in their close relatives, suggesting that shared genes underlie susceptibility to this group of diseases. Early candidate gene association studies yielded a few successes, such as PTPN22, but most such reports now appear to be false-positives. Subsequent genomewide linkage studies identified NLRP1 and XBP1, apparent true GV susceptibility genes involved in immune regulation, and recent genome-wide association studies (GWAS) of GV in Caucasian and Chinese populations have yielded a large number of additional validated GV susceptibility genes. Together, these genes highlight biological systems and pathways that reach from the immune cells to the melanocyte, and provide insights into both disease pathogenesis and potential new targets for both treatment and even prevention of GV and other autoimmune diseases in genetically susceptible individuals.
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Matin R. Vitiligo in adults and children. BMJ CLINICAL EVIDENCE 2011; 2011:1717. [PMID: 21439099 PMCID: PMC3217714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
INTRODUCTION Vitiligo is an acquired skin disorder characterised by white (depigmented) patches in the skin, due to the loss of functioning melanocytes. The extent and distribution of vitiligo often changes during the course of a person's lifetime and its progression is unpredictable. METHODS AND OUTCOMES We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments, and of ultraviolet light treatments, for vitiligo in adults and in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids (oral and topical), oral levamisole, topical immunomodulators, topical vitamin D analogues, ultraviolet A plus psoralen (PUVA [oral or topical]), and ultraviolet B (narrowband).
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Affiliation(s)
- Rubeta Matin
- Centre for Cutaneous Research, Queen Mary University Hospital, London, UK
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Abstract
The acquired depigmenting disorder of vitiligo affects an estimated 1% of the world population and constitutes one of the commonest dermatoses. Although essentially asymptomatic, the psychosocial impact of vitiligo can be severe. The cause of vitiligo remains enigmatic, hampering efforts at successful therapy. The underlying pathogenesis of the pigment loss has, however, been clarified to some extent in recent years, offering the prospect of effective treatment, accurate prognosis and rational preventative strategies. Vitiligo occurs when functioning melanocytes disappear from the epidermis. A single dominant pathway is unlikely to account for all cases of melanocyte loss in vitiligo; rather, it is the result of complex interactions of biochemical, environmental and immunological events, in a permissive genetic milieu. ROS (reactive oxygen species) and H2O2 in excess can damage biological processes, and this situation has been documented in active vitiligo skin. Tyrosinase activity is impaired by excess H2O2 through oxidation of methionine residues in this key melanogenic enzyme. Mechanisms for repairing this oxidant damage are also damaged by H2O2, compounding the effect. Numerous proteins and peptides, in addition to tyrosinase, are similarly affected. It is possible that oxidant stress is the principal cause of vitiligo. However, there is also ample evidence of immunological phenomena in vitiligo, particularly in established chronic and progressive disease. Both innate and adaptive arms of the immune system are involved, with a dominant role for T-cells. Sensitized CD8+ T-cells are targeted to melanocyte differentiation antigens and destroy melanocytes either as the primary event in vitiligo or as a secondary promotive consequence. There is speculation on the interplay, if any, between ROS and the immune system in the pathogenesis of vitiligo. The present review focuses on the scientific evidence linking alterations in ROS and/or T-cells to vitiligo.
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Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol 2010; 131:371-81. [PMID: 21085187 DOI: 10.1038/jid.2010.337] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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.
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Abstract
BACKGROUND Generalized vitiligo is an autoimmune disease of skin pigmentation that is associated with increased prevalence of other autoimmune diseases, particularly autoimmune thyroid disease (AITD; principally Hashimoto's disease and Graves' disease), both in vitiligo patients and their close relatives, suggesting a heritable predisposition involving, in part, shared susceptibility genes. SUMMARY This review summarizes current knowledge of vitiligo epidemiology and genetics, highlighting recent findings from genome-wide approaches to disease gene identification, emphasizing susceptibility loci shared with other autoimmune diseases, particularly AITD, as well as some important differences. CONCLUSIONS Inherited susceptibility to generalized vitiligo involves a number of specific genes, many of which are shared with other autoimmune diseases that are epidemiologically associated with vitiligo, including AITD, confirming a longstanding hypothesis about the genetic basis of these disorders. These genes provide potential therapeutic targets for novel approaches to treatment as well as for approaches to presymptomatic diagnosis and disease prevention in individuals with inherited susceptibility to this group of autoimmune diseases.
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Affiliation(s)
- Richard A Spritz
- Human Medical Genetics Program, University of Colorado School of Medicine, Aurora, Colorado 80113, USA.
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Abstract
Vitiligo occurs in Northern Europe in one of 200 people. The disease can cause significant psychological stress for the affected individual. These patients generate and accumulate massive amounts of H(2)O(2)- and peroxynitrite in the epidermal compartment. Consequently many proteins are oxidized or nitrated, leading in turn to partial or complete loss of functionality. Moreover, presence of DNA damage in the skin as well as in plasma has been shown, while apoptosis is not enhanced. Induction of DNA repair is associated with up-regulated functioning p53 protein. Considering possible genetic predisposition and /or spontaneous mutations, autoimmune reactions in the disease are put forward in the context of oxidative stress. In addition a review of recent and novel treatment modalities including the role of oxidative stress reduction and combined climatotherapy at the Dead Sea in a group are discussed.
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Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet 2010; 42:614-8. [PMID: 20526339 DOI: 10.1038/ng.603] [Citation(s) in RCA: 142] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Accepted: 05/03/2010] [Indexed: 12/14/2022]
Abstract
We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined=1.48x10(-48), OR=1.90; rs9468925, Pcombined=2.21x10(-33), OR=0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined=9.72x10(-17), OR=1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.
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Hegazy M, Darwish H, Darweesh H, El-Shehaby A, Emad Y. Raised serum level of APRIL in patients with systemic lupus erythematosus: Correlations with disease activity indices. Clin Immunol 2010; 135:118-24. [DOI: 10.1016/j.clim.2009.12.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2009] [Revised: 12/03/2009] [Accepted: 12/30/2009] [Indexed: 01/05/2023]
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Smith AG, Sturm RA. Multiple genes and locus interactions in susceptibility to vitiligo. J Invest Dermatol 2010; 130:643-5. [PMID: 20145641 DOI: 10.1038/jid.2009.403] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Refining the position of loci on chromosomes 7 and 9 previously linked with generalized vitiligo or vitiligo-associated autoimmune diseases presenting in families has been performed by high-density single-nucleotide polymorphism (SNP) genotyping. Investigation of the genetic interaction among these loci (and with a previously identified susceptibility gene, NLRP1, on chromosome 17) as risk factors for vitiligo demonstrates the complex nature of this disease.
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Affiliation(s)
- Aaron G Smith
- Melanogenix Group, Division of Molecular Genetics and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
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Genetic variants of the DDR1 gene are associated with vitiligo in two independent Brazilian population samples. J Invest Dermatol 2010; 130:1813-8. [PMID: 20182441 DOI: 10.1038/jid.2010.34] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Vitiligo is a chronic disease characterized by macules devoid of melanin and identifiable melanocytes. Adhesion of melanocytes to the basement membrane by integrin CCN3 is mediated through collagen IV receptor DDR1. We hypothesize that genetic variants of the DDR1 gene are associated with the occurrence of vitiligo. To test this hypothesis, we genotyped 10 DDR1 tag single-nucleotide polymorphisms (SNPs) in 212 trios composed of an affected child and both parents. Associated markers were then genotyped in 134 independent, unrelated individuals with vitiligo and 134 unrelated controls. Allele T of tag SNP rs4618569 was associated with an increased risk for vitiligo in the family trios (P=0.002, odds ratio (OR)=5.27; 95% confidence interval (CI)=1.59-17.40), whereas allele C of tag SNP rs2267641 was associated with an increased risk for vitiligo in both family-based and case-control populations (P=0.01, OR=3.47; 95% CI=1.22-9.17; P=0.04, OR=6.00; 95% CI=1.73-52.33, respectively). The best evidence for association in the trios was obtained for a haplotype composed of risk alleles of markers rs4618569 and rs2267641 (P=0.0006). There was an age-dependent enrichment of rs4618569 T allele and rs2267641 C allele in early-onset affected individuals. In conclusion, we propose DDR1 as a susceptibility gene for vitiligo, possibly implicating a defective cell adhesion in vitiligo pathogenesis.
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