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• W1983805005 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. 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. Generalized vitiligo (GV) is a complex disorder in which acquired, progressive, multifocal loss of pigmentation of skin and hair results from loss of melanocytes from the affected areas (Taïeb and Picardo, 2009Taïeb A. Picardo M. Vitiligo.N Engl J Med. 2009; 360: 160-169Crossref PubMed Scopus (294) Google Scholar; Birlea et al., 2011bBirlea S.A. Spritz R.A. Norris D.A. Vitiligo.in: Wolff K. Fitzpatrick’s Dermatology in General Medicine. 8th ed. 2011Google Scholar). Although the striking phenotype of GV has been recognized for thousands of years (Nordlund et al., 2006Nordlund J.J. Ortonne J.-P. Le Poole I.C. Vitiligo vulgaris.in: Nordlund J.J. Boissy R.E. Hearing V.J. The Pigmentary System. Blackwell, Oxford2006: 551-598Crossref Google Scholar), its underlying pathobiology has remained largely unknown, despite the suggestion of numerous theories (Boissy and Spritz, 2009Boissy R.E. Spritz R.A. Frontiers and controversies in the pathobiology of vitiligo: separating the wheat from the chaff.Exp Dermatol. 2009; 18: 583-585Crossref PubMed Scopus (46) Google Scholar; Picardo and Taïeb, 2010Picardo M. Taïeb A. Vitiligo. Springer, Heidelberg2010Crossref Scopus (42) Google Scholar). Some of the earliest attempts to understand the biology of GV considered its possible genetic basis, in the hope that understanding the genetics would lead to insights into basic pathogenetic mechanisms of disease (Stüttgen, 1950Stüttgen G. Die Vitilgio in erbbiologischer Betrachtung].Z Haut Geschlenkskr. 1950; 9: 451-456PubMed Google Scholar; Teindel, 1950Teindel H. Familiäre.Z Haut Geschlenkskr. 1950; 9: 456-462Google Scholar; Lerner, 1959Lerner A.B. Vitiligo.J Invest Dermatol. 1959; 32: 285-310Crossref PubMed Scopus (262) Google Scholar). Over the next four decades, various types of genetic studies aimed to discover genes involved in mediating GV susceptibility, with limited success. However, recently genome-wide genetic association studies have succeeded in identifying a veritable cornucopia of GV susceptibility genes, encoding components of biological networks that largely regulate elements of the immune system and their targeting and destruction of melanocytes. Probably the earliest evidence relating to the genetic basis of vitiligo was the 1855 description by Addison of a patient with idiopathic adrenal insufficiency (now known as Addison's disease), GV, and pernicious anemia (Addison, 1855Addison T. On the constitutional and local effects of disease of the suprarenal capsules.in: A collection of the published writing of the late Thomas Addison, M.D., physician to Guy’s Hospital, New Sydenham Society, London 1868. Reprinted in Med Classics 1937 21855: 244-293Google Scholar). Over the next century numerous case reports described co-occurrence of GV and various other autoimmune diseases, and in 1908 Claude and Gourgerot, 1908Claude H. Gourgerot H. Insuffisiance pluriglandulaire endocrinienne.J Physiol Pathol Gen. 1908; 10: 469-480Google Scholar) suggested the likelihood of a causal connection among autoimmune diseases that tended to occur concomitantly. In 1926, Schmidt codified the concomitant occurrence of Addison's disease and autoimmune thyroid disease, in what came to be called “Schmidt syndrome” (Schmidt, 1926Schmidt M. Eine biglanduiare Erkrankung (Nebennieren und Schilddruse) bei Morbus Addisonii].Verh Dtsch Ges Pathol. 1926; 21: 212-221Google Scholar), and in 1980, Neufeld and Blizzard re-classified the so-called “autoimmune polyglandular syndromes” (APS), denoting a rare autosomal recessive form (sometimes including GV) as APS-1, denoting Schmidt syndrome (sometimes including GV) as APS-2, denoting concomitant occurrence of autoimmune thyroid disease with at least one other autoimmune disease (again, often including GV) as APS-3, and denoting all other combinations of autoimmune diseases as APS-4 (Neufeld and Blizzard, 1980Neufeld M. Blizzard R.M. Polyglandular autoimmune diseases. In: Symposium on Autoimmune Aspects of Endocrine Disorders.in: Pinchera A. Doniach D. Fenzi G.F. 1980: 357-365Google Scholar). Although there have been a number of subsequent attempts to refine the APS classification, except for APS-1 (now renamed APECED; autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy, resulting from mutations in the AIRE gene), this system is no longer widely used. Instead, it has become clear that “multiple autoimmune disease” is more complex, and that GV is part of a more general autoimmune disease diathesis. Indeed, the frequencies of many other autoimmune diseases, particularly including autoimmune thyroid disease (Hashimoto's thyroiditis and Graves’ disease), adult-onset type 1 diabetes mellitus, rheumatoid arthritis, psoriasis, pernicious anemia, Addison's disease, and systemic lupus erythematosus (SLE), are elevated among GV patients (Alkhateeb et al., 2003Alkhateeb A. Fain P.R. Thody A. et al.Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (523) Google Scholar; Laberge et al., 2005Laberge G. Mailloux C.M. Gowan K. et al.Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo.Pigment Cell Res. 2005; 18: 300-305Crossref PubMed Scopus (145) Google Scholar; Sun et al., 2006Sun X. Xu A. Wei X. et al.Genetic epidemiology of vitiligo: a study of 815 probands and their families from south China.Int J Dermatol. 2006; 45: 1176-1181Crossref PubMed Scopus (53) Google Scholar). Furthermore, the frequencies of these same autoimmune diseases are elevated among the first-degree relatives of GV patients, even those who do not have GV (Alkhateeb et al., 2003Alkhateeb A. Fain P.R. Thody A. et al.Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (523) Google Scholar; Laberge et al., 2005Laberge G. Mailloux C.M. Gowan K. et al.Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo.Pigment Cell Res. 2005; 18: 300-305Crossref PubMed Scopus (145) Google Scholar). This has led to the belief that general susceptibility to autoimmunity is a complex trait involving various shared susceptibility genes, whereas other genes and exposure to unknown environmental triggers determine the occurrence of GV and other specific autoimmune diseases in individual patients (Spritz, 2008Spritz R.A. The genetics of generalized vitiligo.Curr Dir Autoimmun. 2008; 10: 244-257Crossref PubMed Scopus (95) Google Scholar). In addition, genetic epidemiological studies have addressed the likely mode of inheritance of GV. Although there had been a number of previous case reports describing the occurrence of GV in occasional relatives, perhaps the first to address the inheritance of GV specifically were Stüttgen, 1950Stüttgen G. Die Vitilgio in erbbiologischer Betrachtung].Z Haut Geschlenkskr. 1950; 9: 451-456PubMed Google Scholar and Teindel, 1950Teindel H. Familiäre.Z Haut Geschlenkskr. 1950; 9: 456-462Google Scholar, who described multigenerational families with multiple cases of GV (“multiplex families”) and other autoimmune diseases, concluding that autosomal dominant inheritance seemed likely. On the basis of a survey of 128 vitiligo patients, Lerner, 1959Lerner A.B. Vitiligo.J Invest Dermatol. 1959; 32: 285-310Crossref PubMed Scopus (262) Google Scholar noted that 38% reported affected relatives, and concluded that the “disease is often transmitted as a dominant trait.” However, although many subsequent patient surveys around the world confirmed frequent clustering of vitiligo cases within families (Mehta et al., 1973Mehta N.R. Shah K.C. Theodore C. et al.Epidemiological study of vitiligo in Surat area, south Gujarat.Indian J Med Res. 1973; 61: 145-154PubMed Google Scholar; Howitz et al., 1977Howitz J. Brodthagen H. Schwartz M. et al.Prevalence of vitiligo: epidemiological survey of the isle of Bornholm, Denmark.Arch Dermatol. 1977; 113: 47-52Crossref PubMed Scopus (238) Google Scholar; Obe, 1984Obe W.K. Vitiligo in Zimbabwe.Cent Afr J Med. 1984; 30: 259-264PubMed Google Scholar; Das et al., 1985Das S.K. Majumder P.P. Chakraborty R. et al.Studies on vitiligo. I. Epidemiological profile in Calcutta, India.Genet Epidemiol. 1985; 2: 71-78Crossref PubMed Scopus (108) Google Scholar; Bhatia et al., 1992Bhatia P.S. Mohan L. Pandey O.N. et al.Genetic nature of vitiligo.J Dermatol Sci. 1992; 4: 180-184Abstract Full Text PDF PubMed Scopus (42) Google Scholar; Majumder et al., 1993Majumder P.P. Nordland J.J. Nath S.P. Pattern of familial aggregation of vitiligo.Arch Dermatol. 1993; 129: 994-998Crossref PubMed Scopus (149) Google Scholar; Kim et al., 1998Kim S.M. Chung H.S. Hann S.-K. The genetics of vitiligo in Korean patients.Internat J Dermatol. 1998; 38: 908-910Crossref Scopus (23) Google Scholar; Alkhateeb et al., 2003Alkhateeb A. Fain P.R. Thody A. et al.Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (523) Google Scholar; Sun et al., 2006Sun X. Xu A. Wei X. et al.Genetic epidemiology of vitiligo: a study of 815 probands and their families from south China.Int J Dermatol. 2006; 45: 1176-1181Crossref PubMed Scopus (53) Google Scholar), a single-locus Mendelian pattern of inheritance was not supported, and most favored a polygenic, multifactorial model involving multiple genes and also environmental risk factors, what is now termed a “complex trait”. A major environmental component in GV is also indicated by its limited concordance in monozygotic twins; among 22 such twin pairs, Alkhateeb et al., 2003Alkhateeb A. Fain P.R. Thody A. et al.Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214Crossref PubMed Scopus (523) Google Scholar reported a concordance of only 23%, underscoring the importance of environmental triggers in disease pathogenesis. The earliest analyses testing the involvement of specific genes in the pathogenesis of GV were candidate gene association studies, of HLA (Retornaz et al., 1976Retornaz G. Betuel H. Ortonne J.P. et al.HL-A antigens and vitiligo.Br J Dermatol. 1976; 95: 173-175Crossref PubMed Scopus (33) Google Scholar), ABO (Kareemullah et al., 1977Kareemullah L. Taneja V. Begum S. et al.Association of ABO blood groups and vitiligo.J Med Genet. 1977; 14: 211-213Crossref PubMed Scopus (7) Google Scholar), and other blood groups (Wasfi et al., 1980Wasfi A.I. Saha N. El Munshid H.A. et al.Genetic association in vitiligo: ABO, MNSs, Rhesus, Kell and Duffy blood groups.Clin Genet. 1980; 17: 415-417Crossref PubMed Scopus (13) Google Scholar), and were generally negative. A large number of “positive” candidate gene associations with GV have been reported subsequently (reviewed in Birlea et al., 2011aBirlea S.A. Jin Y. Bennett D.C. et al.Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.J Invest Dermatol. 2011; 131: 371-381Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). However, candidate gene association studies of complex diseases have generally proven to be highly subject to false-positive artifacts, principally due to occult ethnic differences between cases and controls (population stratification) and inadequate correction for multiple testing (Hirschhorn et al., 2002Hirschhorn J.N. Lohmueller K. Byrne E. et al.A comprehensive review of genetic association studies.Genet Med. 2002; 4: 45-60Crossref PubMed Scopus (1401) Google Scholar; Freedman et al., 2004Freedman M.L. Reich D. Penney K.L. et al.Assessing the impact of population stratification on genetic association studies.Nat Genet. 2004; 36: 388-393Crossref PubMed Scopus (633) Google Scholar), and thus have fallen into general disfavor. Except for HLA and PTPN22, most candidate gene associations reported for GV have not been confirmed by subsequent studies (reviewed in Birlea et al., 2011aBirlea S.A. Jin Y. Bennett D.C. et al.Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.J Invest Dermatol. 2011; 131: 371-381Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Genome-wide linkage and association studies are not biased by a priori biological hypotheses and are less subject to methodological pitfalls than are candidate gene approaches. Genetic linkage studies are best suited to detect relatively rare disease susceptibility alleles with large effects, as in multiplex families. Although genetic linkage studies are typically carried out genome-wide, in fact, the first linkage analysis reported for GV was a negative study, testing linkage of a candidate gene, MITF (Tripathi et al., 1999Tripathi R.K. Flanders D.J. Young T.L. et al.Microphthalmia-associated transcription factor (MITF) locus lacks linkage to human vitiligo or osteopetrosis: an evaluation.Pigment Cell Res. 1999; 12: 187-192Crossref PubMed Scopus (18) Google Scholar). The first direct genome-wide linkage study of GV, in a unique large Caucasian kindred with apparent autosomal dominant inheritance with incomplete penetrance, detected linkage in chromosome 1p31.3–p32.2 (“AIS1”; Alkhateeb et al., 2002Alkhateeb A. Stetler G.L. Old W. et al.Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2.Hum Mol Genet. 2002; 11: 661-667Crossref PubMed Scopus (106) Google Scholar). Subsequent DNA sequence analysis of genes in the chromosome 1p linkage interval identified a transcriptional regulatory variant of FOXD3, which encodes Forkhead box D3), a key regulator of melanoblast lineage differentiation and development (Alkhateeb et al., 2005Alkhateeb A. Fain P. Spritz R.A. Candidate functional promoter variant in the FOXD3 melanoblast developmental regulator gene in autosomal dominant vitiligo.J Invest Dermatol. 2005; 125: 388-991PubMed Scopus (49) Google Scholar). Genome-wide linkage studies of numerous other Caucasian multiplex GV families identified additional linkage signals on chromosomes 7, 8, 9, 11, 13, 17, 19, and 22 (Fain et al., 2003Fain P.R. Gowan K. LaBerge G.S. et al.A genomewide screen for autoimmune vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci.Am J Hum Genet. 2003; 72: 1560-1564Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar; Spritz et al., 2004Spritz R.A. Gowan K. Bennett D.C. et al.Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis.Am J Hum Genet. 2004; 74: 188-191Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). The strongest of these signals, on chromosome 17p13, coincided with SLEV1, a linkage signal for systemic lupus erythematosus detected in families that also included at least one relative with GV (Nath et al., 2001Nath S.K. Kelly J.A. Namjou B. et al.Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus.Am J Hum Genet. 2001; 69: 1401-1406Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar) or other autoimmune diseases (Johansson et al., 2004Johansson C.M. Zunec R. Garcia M.A. et al.Chromosome 17p12-q11 harbors susceptibility loci for systemic lupus erythematosus.Hum Genet. 2004; 115: 230-238Crossref PubMed Scopus (30) Google Scholar). Targeted family-based genetic association analysis of single-nucleotide polymorphisms (SNPs) spanning the chromosome 17p linkage interval identified the corresponding gene as NALP1 (now renamed NLRP1), encoding NACHT, LRR, and PYD domains-containing protein 1 (Jin et al., 2007bJin Y. Mailloux C.M. Gowan K. et al.NALP1 and vitiligo-associated multiple autoimmune disease.N Engl J Med. 2007; 365: 10-18Google Scholar), a key regulator of the innate immune system that apparently functions as a sentinel for bacterial infection in the skin (Lamkanfi and Dixit, 2009Lamkanfi M. Dixit V.M. Inflammasomes: guardians of cytosolic sanctity.Immunol Rev. 2009; 227: 95-105Crossref PubMed Scopus (287) Google Scholar). Several studies have subsequently confirmed association of NLRP1 with GV (Jin et al., 2007aJin Y. Birlea S.A. Fain P.R. et al.Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population.J Invest Dermatol. 2007; 127: 2558-2562Crossref PubMed Scopus (115) Google Scholar; Alkhateeb and Qarqaz, 2010Alkhateeb A. Qarqaz F. Genetic association of NALP1 with generalized vitiligo in Jordanian Arabs.Arch Dermatol Res. 2010; 302: 631-634Crossref PubMed Scopus (26) Google Scholar), and also with type 1 diabetes (Magitta et al., 2009Magitta N.F. Bøe Wolff A.S. Johansson S. et al.A coding polymorphism in NALP1 confers risk for autoimmune Addison′s disease and type 1 diabetes.Genes Immun. 2009; 10: 120-124Crossref PubMed Scopus (147) Google Scholar), Addison's disease (Magitta et al., 2009Magitta N.F. Bøe Wolff A.S. Johansson S. et al.A coding polymorphism in NALP1 confers risk for autoimmune Addison′s disease and type 1 diabetes.Genes Immun. 2009; 10: 120-124Crossref PubMed Scopus (147) Google Scholar; Zurawek et al., 2010Zurawek M. Fichna M. Januszkiewicz-Lewandowska D. et al.A coding variant in NLRP1 is associated with autoimmune Addison′s disease.Hum Immunol. 2010; 71: 530-534Crossref PubMed Scopus (67) Google Scholar), celiac disease (Pontillo et al., 2011Pontillo A. Vendramin A. Catamo E. et al.The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease.Am J Gastroenterol. 2011; 106: 539-544Crossref PubMed Scopus (77) Google Scholar), systemic sclerosis (Dieudé et al., 2010Dieudé P. Guedj M. Wipff J. et al.NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.Ann Rheum Dis. 2010; 70: 668-674Crossref PubMed Scopus (80) Google Scholar), and perhaps inflammatory bowel disease (De Iudicibus et al., 2011De Iudicibus S. Stocco G. Martelossi S. et al.Genetic predictors of glucocorticoid response in pediatric patients with inflammatory bowel diseases.J Clin Gastroenterol. 2011; 45: e1-e7Crossref PubMed Scopus (48) Google Scholar). Parallel genetic linkage studies of GV in Han Chinese detected linkage signals on chromosomes 1, 4, 6, 14, and 22 (Chen et al., 2005Chen J.J. Huang W. Gui J.P. et al.A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families.Am J Hum Genet. 2005; 76: 1057-1065Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar; Liang et al., 2007Liang Y. Yang S. Zhou Y. et al.Evidence for two susceptibility loci on chromosomes 22q12 and 6p21-p22 in Chinese generalized vitiligo families.J Invest Dermatol. 2007; 127: 2552-2557Crossref PubMed Scopus (29) Google Scholar). These linkage signals generally did not correspond to those detected in Caucasian families, suggesting that different genes might underlie GV susceptibility in these different populations. By candidate gene association analysis of several genes located within the chromosome 22q12.1–12.3 linkage peak, Ren et al., 2009Ren Y. Yang S. Xu S. et al.Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo.PLoS Genet. 2009; 5: e1000523Crossref PubMed Scopus (64) Google Scholar subsequently identified XBP1, encoding transcription factor X-box binding protein 1, which activates HLA class II gene expression, regulates plasma cell differentiation, and mediates inflammatory response to endoplasmic reticulum stress. Additional support for involvement of XBP1 in the pathogenesis of GV came from a subsequent genome-wide association study (GWAS) of Caucasians (Birlea et al., 2011aBirlea S.A. Jin Y. Bennett D.C. et al.Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.J Invest Dermatol. 2011; 131: 371-381Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar), and XBP1 has been independently associated with genetic risk of Crohn's disease (Kaser et al., 2008Kaser A. Lee A.H. Franke A. et al.XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease.Cell. 2008; 134: 743-756Abstract Full Text Full Text PDF PubMed Scopus (1079) Google Scholar). Genome-wide association studies (GWAS) are best suited to detect relatively common disease susceptibility alleles with modest effects, as may be most relevant to typical singleton cases of a complex disease such as GV. Of particular importance, GWAS can adequately correct for both population stratification and multiple testing (Hirschhorn et al., 2002Hirschhorn J.N. Lohmueller K. Byrne E. et al.A comprehensive review of genetic association studies.Genet Med. 2002; 4: 45-60Crossref PubMed Scopus (1401) Google Scholar; Freedman et al., 2004Freedman M.L. Reich D. Penney K.L. et al.Assessing the impact of population stratification on genetic association studies.Nat Genet. 2004; 36: 388-393Crossref PubMed Scopus (633) Google Scholar), and so are currently considered the “gold standard” for identifying complex trait susceptibility genes. The first GV GWAS (Birlea et al., 2010Birlea S.A. Gowan K. Fain P.R. et al.Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8.J Invest Dermatol. 2010; 130: 798-803Crossref PubMed Scopus (65) Google Scholar) involved a “special population”, an isolated village with a very high prevalence of GV located in the mountains of northwestern Romania (Birlea et al., 2008Birlea S.A. Fain P.R. Spritz R.A. A Romanian population isolate with high frequency of vitiligo and associated autoimmune diseases.Arch Dermatol. 2008; 144: 310-316Crossref PubMed Scopus (55) Google Scholar). This analysis detected GV association with SNPs in distal chromosome 6q27, in the vicinity of IDDM8, a linkage and association signal for type I diabetes mellitus and rheumatoid arthritis. A subsequent, much larger GWAS in Caucasians detected at least 13 different GV susceptibility loci (Table 1; Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.N Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar,Jin et al., 2010bJin Y. Birlea S.A. Fain P.R. et al.Common variants in FOXP1 are associated with generalized vitiligo.Nat Genet. 2010; 42: 576-578Crossref PubMed Scopus (80) Google Scholar), and confirmed three others that had been reported in previous candidate gene studies (Birlea et al., 2011aBirlea S.A. Jin Y. Bennett D.C. et al.Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.J Invest Dermatol. 2011; 131: 371-381Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). A parallel GV GWAS in Chinese (Quan et al., 2010Quan C. Ren Y.Q. Xiang L.H. et al.Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010; 42: 614-618Crossref PubMed Scopus (145) Google Scholar) detected two association signals, one or both of which were among those detected in Caucasians (Table 1). In both the Caucasian and Chinese studies, strong GV association signals were detected in the major histocompatibility complex (MHC) on chromosome 6p21.3. In Caucasians, independent associations were detected in both the MHC class I and class II gene regions. In the class I region, the major association signal was in the vicinity of HLA-A, in strong linkage disequilibrium with HLA-A*02. In the class II region, the major association signal was located between HLA–DRB1 and HLA–DQA1, in moderate linkage disequilibrium with HLA-DRB1*04 (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.N Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar). These results are thus consistent with previous reports of association of GV with both HLA-A*02 (Liu et al., 2007Liu J.B. Li M. Chen H. et al.Association of vitiligo with HLA-A2: a meta-analysis.J Eur Acad Dermatol Venereol. 2007; 21: 205-213Crossref PubMed Scopus (55) Google Scholar) and HLA–DRB1*04 (Fain et al., 2006Fain P.R. Babu S.R. Bennett D.C. et al.HLA class II haplotype DRB1*04-DQB1*0301 contributes to risk of familial generalized vitiligo and early disease onset.Pigment Cell Res. 2006; 19: 51-57Crossref PubMed Scopus (48) Google Scholar) alleles. However, in Chinese, the major MHC association signal was in the class III gene region, with some evidence for additional association in the class II gene region (Quan et al., 2010Quan C. Ren Y.Q. Xiang L.H. et al.Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010; 42: 614-618Crossref PubMed Scopus (145) Google Scholar).Table 1Loci with confirmed involvement in GV susceptibility on the basis of genome-wide studies1Adapted from Spritz (2011).ChromosomeGeneProteinFunctionCausal variantOther autoimmune disease associations1p36.23REREAtrophin-like protein 1Regulates apoptosis1p13.2PTPN22Lymphoid-specific protein tyrosine phosphatase nonreceptor type 22Regulates TCR signalingR620WType 1 diabetes, SLE, Graves’ disease, rheumatoid arthritis, Addison's disease, psoriasis, inflammatory bowel disease2q33.2CTLA42Numerous studies have indicated that CTLA4 is only associated with GV in patients who also have other autoimmune diseases, suggesting that apparent association of CLTA4 with GV is secondary to epidemiological association with these other diseases.Cytotoxic T-lymphocyte antigen 4Inhibits T cellsType 1 diabetes, Graves’ disease, Hashimoto's thyroiditis, inflammatory bowel disease, SLE3p13FOXP1Forkhead box P1Regulates lymphoid cell development3q28LPPLIM domain-containing preferred translocation partner in lipomaUnknownCeliac disease, rheumatoid arthritis5q22.1TSLPThymic stromal lymphoproteinRegulates T-cell and dendritic cell maturation6p21.3MHC class I (HLA-A)HLA-α chainPresents peptide antigens*02:01ManyMHC class II3The MHC class II region is associated with both GV susceptibility and age of onset.UnknownManyMHC class IIIUnknownMany6q27CCR6C-C chemokine receptor type 6Regulates B-cell differentiation, function of dendritic and Th17 cellsInflammatory bowel disease, rheumatoid arthritis, Graves’ disease10p15.1IL2RAIL-2 receptor α-chainRegulates lymphocyte response to bacteria via IL2Type 1 diabetes, Graves’ disease, multiple sclerosis, rheumatoid arthritis, SLE11q14.3TYRTyrosinaseKey enzyme of melanin biosynthesisR402Q14q12GZMBGranzyme BMediates target cell apoptosis by cytotoxic T cells and natural killer cells, activation-induced cell death of effector Th2 cells17p13.2NLRP1NACHT, LRR, and PYD domains-containing protein 1Type 1 diabetes, Addison's disease, celiac disease, systemic sclerosis21q22.3UBASH3AUbiquitin-associated and SH3 domain-containing ARegulates TCR signalingType 1 diabetes22q12.1XBP1X-box binding protein 1Regulates expression of HLA class II genes, IL6, B-cell and plasma cell differentiationCrohn's disease22q13.1C1QTNF6C1q and tumor necrosis factor-related protein 6UnknownType 1 diabetes, rheumatoid arthritisXp11.23FOXP3Forkhead box P3Regulates regulatory T cellsDefective gene in immunodysregulation polyendocrinopathy enteropathy X-linked syndromeAbbreviations: GV, generalized vitiligo; MHC, major histocompatibility complex; SLE, systemic lupus erythematosus.1 Adapted from Spritz, 2011Spritz R.A. Recent progress in the genetics of generalized vitiligo.J Genet Genomics. 2011; 38: 271-278Crossref PubMed Scopus (45) Google Scholar.2 Numerous studies have indicated that CTLA4 is only associated with GV in patients who also have other autoimmune diseases, suggesting that apparent association of CLTA4 with GV is secondary to epidemiological association with these other diseases.3 The MHC class II region is associated with both GV susceptibility and age of onset. Open table in a new tab Abbreviations: GV, generalized vitiligo; MHC, major histocompatibility complex; SLE, systemic lupus erythematosus. Perhaps more important, these two large-scale GV GWASs also detected association with a number of non-MHC loci, almost all of which encode immunoregulatory proteins. The Caucasian GWAS (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.N Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar,Jin et al., 2010bJin Y. Birlea S.A. Fain P.R. et al.Common variants in FOXP1 are associated with generalized vitiligo.Nat Genet. 2010; 42: 576-578Crossref PubMed Scopus (80) Google Scholar) detected associations with SNPs in at least 10 non-MHC loci: TYR (tyrosinase), PTPN22 (lymphoid-specific protein tyrosine phosphatase nonreceptor type 22), RERE (arginine-glutamic acid dipeptide (RE) repeats protein; atrophin-like protein 1), FOXP1 (forkhead box P1), LPP (LIM domain-containing preferred translocation partner in lipoma), IL2RA (IL-2 receptor alpha chain), GZMB (granzyme B), UBASH3A (ubiquitin-associated and SH3 domain-containing A), C1QTNF6 (C1q and tumor necrosis factor-related protein 6), and CCR6 (C-C chemokine receptor type 6). This last gene is located very close to the 6q27 association signal detected in the Romanian village (Birlea et al., 2010Birlea S.A. Gowan K. Fain P.R. et al.Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8.J Invest Dermatol. 2010; 130: 798-803Crossref PubMed Scopus (65) Google Scholar), and was the only non-MHC locus detected in the Chinese GWAS (Quan et al., 2010Quan C. Ren Y.Q. Xiang L.H. et al.Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.Nat Genet. 2010; 42: 614-618Crossref PubMed Scopus (145) Google Scholar). The Caucasian GWAS also provided evidence of association of GV with additional loci previously suggested as candidate genes for GV: XBP1 (see above), FOXP3 (forkhead box P3), TSLP (thymic stromal lymphoprotein), and CTLA4 (cytotoxic T-lymphocyte antigen 4), although as in previous studies association of GV with CTLA4 appeared to perhaps reflect primary association with other concomitant autoimmune diseases in the GV cases, rather than with GV itself (Birlea et al., 2011aBirlea S.A. Jin Y. Bennett D.C. et al.Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP.J Invest Dermatol. 2011; 131: 371-381Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Among the most illuminating associations with GV are those of MHC class I and TYR, which together highlight one of the pathways by which the immune system “sees” and thus targets melanocytes. The MHC class I association in Caucasians with GV is with SNP rs12206499, which tags HLA-A*02 (predominantly HLA-A*02:01), while the TYR association with GV is with the major (R; Arg) allele of the R402Q polymorphism (SNP rs1126809) that is relatively common among Caucasians (minor allele frequency 0.22–0.40), but is rare in other populations (Tripathi et al., 1991Tripathi R.K. Giebel L.B. Strunk K.M. et al.A polymorphism of the human tyrosinase gene that is associated with temperature-sensitive enzymatic activity.Gene Expr. 1991; 1: 103-110PubMed Google Scholar). In contrast, the minor (Q; Gln) allele of the TYR R402Q polymorphism is associated with susceptibility to malignant melanoma (Gudbjartsson et al., 2008Gudbjartsson D.F. Sulem P. Stacey S.N. et al.ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma.Nat Genet. 2008; 40: 886-891Crossref PubMed Scopus (265) Google Scholar; Bishop et al., 2009Bishop T.D. Demenais F. Iles M.M. et al.Genome-wide association study identifies three loci associated with melanoma risk.Nat Genet. 2009; 41: 920-925Crossref PubMed Scopus (370) Google Scholar), while HLA-A*02 is associated with relatively favorable response to melanoma immunotherapy (Mitchell et al., 1992Mitchell M.S. Harel W. Groshen S. Association of HLA phenotype with response to active specific immunotherapy of melanoma.J Clin Oncol. 1992; 10: 1158-1164PubMed Google Scholar). Tyrosinase is a major GV autoantigen presented to the immune system on the surface of melanocytes and melanoma cells by HLA class I molecules, principally HLA-A*02. One of the important epitopes presented by HLA-A*02 is a modified tyrosinase nonapeptide, YMDGTMSQV (Skipper et al., 1996Skipper J.C.A. Hendrickson R.C. Gulden P.H. et al.An HLA-A2-restricted tyrosinase antigen on melanoma cells results from posttranslational modification and suggests a novel pathway for processing of membrane proteins.J Exp Med. 1996; 183: 527-534Crossref PubMed Scopus (378) Google Scholar). However, the variant 402Q form of tyrosinase is hypoglycosylated (Toyofuku et al., 2001Toyofuku K. Wada I. Spritz R.A. et al.The molecular basis of oculocutaneous albinism type 1 (OCA1): sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation.Biochem J. 2001; 355: 259-269Crossref PubMed Scopus (94) Google Scholar), which in turn would prevent the modification that is essential for its antigenic presentation by HLA-A*02. As the result, tyrosinase-402R likely makes a quantitatively greater contribution than tyrosinase-402Q to presentation of antigenic tyrosinase by HLA-A*02. Together, these findings indicate an apparent inverse relationship between genetic susceptibility to GV and genetic susceptibility to malignant melanoma as mediated by TYR and HLA-A*02 (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.N Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar), suggesting that GV may represent a dysregulated mechanism of immune surveillance against malignant melanoma, with TYR R402Q modulating immune recognition of melanocytes by modulating availability of tyrosinase peptide for presentation by HLA-A*02 (Spritz, 2010Spritz R.A. The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma.Genome Med. 2010; 2: 78Crossref PubMed Scopus (70) Google Scholar). In addition to primary searches for genes that influence disease susceptibility per se, genome-wide approaches can also be used to identify genes that influence the natural history of disease. Such an approach has recently been taken to identify a locus that contributes to GV age of onset (Jin et al., 2011Jin Y. Birlea S.A. Fain P.R. et al.Genome-wide analysis identifies a quantitative trait locus in the MHC class II region associated with generalized vitiligo age of onset.J Invest Dermatol. 2011; 131: 1308-1312Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). These authors’ reanalyzed their previous GV GWAS data set, considering only the affected individuals, in whom GV age of onset was assessed as a quantitative trait. This analysis identified a major GV age of onset locus in the MHC class II region, apparently reflecting the same locus that was associated with GV susceptibility (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.N Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar), while none of the other loci that had been associated with GV susceptibility per se were associated with age of onset. These results indicate that some loci likely mediate GV susceptibility per se, whereas other loci, particularly variation in the MHC class II region, might mediate response to environmental triggers encountered over the course of life, thereby influencing age of disease onset. For GV as for many other complex diseases, application of genome-wide approaches, particularly GWAS, has resulted in rapid progress in identifying true disease susceptibility genes, while most genes suggested as a priori biologically based candidates have remained unconfirmed. Accordingly, for GV as for many other diseases, we have entered a new era of understanding the true underlying pathobiology, which in the case of GV appears to be predominantly autoimmune. Furthermore, many of the genes that are genetically associated with GV are also genetically associated with some of the other autoimmune diseases with which GV is epidemiologically associated, confirming the longstanding hypothesis that these epidemiological associations reflect underlying shared causal elements (Claude and Gourgerot, 1908Claude H. Gourgerot H. Insuffisiance pluriglandulaire endocrinienne.J Physiol Pathol Gen. 1908; 10: 469-480Google Scholar). The studies carried out so far have identified a plethora of new biological pathways that constitute potential targets for therapeutic intervention and perhaps even disease prevention. However, these findings only scratch the surface, accounting for a relatively small portion of total disease risk. Larger genome-wide studies can be expected to identify even more GV susceptibility genes and thus shed even more light on the nature of the disease, and perhaps even provide clues to environmental triggers. Moreover, for only a few of the GV susceptibility genes found thus far have the corresponding underlying causal variants been identified; this will require extensive DNA sequencing of large numbers of GV patients, careful bioinformatics analysis, and targeted functional studies to assess the effects of specific variants, both individually and in combination. Nevertheless, the way forward is now clear, with many doors opening to new understanding and new opportunities for treating patients with GV. This work was supported in part by grants R01 AR45585 and R01 AR056292 from the National Institutes of Health. Thanks to PR Fain, SA Birlea, and Y Jin for comments on the manuscript." @default.
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• W1983805005 title "Six Decades of Vitiligo Genetics: Genome-Wide Studies Provide Insights into Autoimmune Pathogenesis" @default.
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