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.
Key points
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Vitiligo is a complex disorder (also termed polygenic and multifactorial), reflecting simultaneous contributions of multiple genetic risk factors and environmental triggers.
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Large-scale genomewide association studies, principally in European-derived whites and in Chinese, have discovered approximately 50 different genetic loci that contribute to vitiligo risk, some of which also contribute to other autoimmune diseases that are epidemiologically associated with vitiligo. At many of these vitiligo susceptibility loci the corresponding relevant genes have now been identified and, for some of these genes, the specific DNA sequence variants that contribute to vitiligo risk are also now known.
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A large fraction of these genes encode proteins involved in immune regulation, several others play roles in cellular apoptosis, and still others are involved in regulating functions of melanocytes.
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Although many of the specific biologic mechanisms through which these genetic factors operate to cause vitiligo remain to be elucidated, it is now clear that vitiligo is an autoimmune disease involving a complex relationship between programming and function of the immune system, aspects of the melanocyte autoimmune target, and dysregulation of the immune response.
Introduction, background, and genetic epidemiology
The disorder now known as vitiligo was first described by Claude Nicolas Le Cat in 1765. However, the first specific consideration of a genetic component in vitiligo did not come until 1950, when Stűttgen and Teindel simultaneously reported a total of 8 families with multiple relatives affected by vitiligo. Stűttgen noted that, in his affected family, vitiligo seemed to exhibit dominant inheritance after intermarriage to a family with apparent recessive thyroid disease, a very early recognition of what would now be considered complex (polygenic, multifactorial) inheritance. Mohr, Siemens, and Vogel subsequently reported concordant identical twin-pairs affected by vitiligo, pointing to a major role for genetic factors. Early clinical case series reported a frequency of vitiligo in probands’ relatives of 11% to 38%, highlighting the importance of genetic factors even in typical vitiligo cases.
Nevertheless, formal genetic epidemiologic studies of vitiligo came much later. Hafez and colleagues, and Das and colleagues, suggested a polygenic, multifactorial mode of inheritance, and estimated vitiligo heritability at 46% to 72%. Subsequent investigations likewise supported a polygenic, multifactorial model, with heritability approximately 50%. A twin study of vitiligo in European-derived whites found that the concordance of vitiligo was 23% in monozygotic twins, underscoring the importance of nongenetic factors as well as genetic factors in vitiligo pathogenesis. In this same study, large-scale genetic epidemiologic analyses indicated that in European-derived whites the overall frequency of vitiligo in probands’ first-degree relatives was 7%, with the risk 7.8% in probands’ parents and 6.1% in siblings, consistent with polygenic, multifactorial inheritance and age-dependency of vitiligo onset. Importantly, among vitiligo probands’ affected relatives, the frequency of vitiligo was equal in male and female subjects, eliminating the female sex bias found in most vitiligo clinical case series. Moreover, a careful study of families with multiple relatives affected by vitiligo showed earlier age-of-onset and greater skin surface involvement than in singleton cases, as well as greater frequency of other autoimmune diseases, suggesting that in such multiplex families genes likely contribute more to vitiligo risk than in singleton cases.
Introduction, background, and genetic epidemiology
The disorder now known as vitiligo was first described by Claude Nicolas Le Cat in 1765. However, the first specific consideration of a genetic component in vitiligo did not come until 1950, when Stűttgen and Teindel simultaneously reported a total of 8 families with multiple relatives affected by vitiligo. Stűttgen noted that, in his affected family, vitiligo seemed to exhibit dominant inheritance after intermarriage to a family with apparent recessive thyroid disease, a very early recognition of what would now be considered complex (polygenic, multifactorial) inheritance. Mohr, Siemens, and Vogel subsequently reported concordant identical twin-pairs affected by vitiligo, pointing to a major role for genetic factors. Early clinical case series reported a frequency of vitiligo in probands’ relatives of 11% to 38%, highlighting the importance of genetic factors even in typical vitiligo cases.
Nevertheless, formal genetic epidemiologic studies of vitiligo came much later. Hafez and colleagues, and Das and colleagues, suggested a polygenic, multifactorial mode of inheritance, and estimated vitiligo heritability at 46% to 72%. Subsequent investigations likewise supported a polygenic, multifactorial model, with heritability approximately 50%. A twin study of vitiligo in European-derived whites found that the concordance of vitiligo was 23% in monozygotic twins, underscoring the importance of nongenetic factors as well as genetic factors in vitiligo pathogenesis. In this same study, large-scale genetic epidemiologic analyses indicated that in European-derived whites the overall frequency of vitiligo in probands’ first-degree relatives was 7%, with the risk 7.8% in probands’ parents and 6.1% in siblings, consistent with polygenic, multifactorial inheritance and age-dependency of vitiligo onset. Importantly, among vitiligo probands’ affected relatives, the frequency of vitiligo was equal in male and female subjects, eliminating the female sex bias found in most vitiligo clinical case series. Moreover, a careful study of families with multiple relatives affected by vitiligo showed earlier age-of-onset and greater skin surface involvement than in singleton cases, as well as greater frequency of other autoimmune diseases, suggesting that in such multiplex families genes likely contribute more to vitiligo risk than in singleton cases.
Relationship to other autoimmune diseases
The genetic basis of vitiligo is deeply intertwined with the genetic basis of other autoimmune diseases with which vitiligo is epidemiologically associated. Indeed, the earliest clue to the autoimmune origin of vitiligo came in the original 1855 report of Addison disease, which included a patient with idiopathic adrenal insufficiency, generalized vitiligo, and pernicious anemia, a co-occurrence of autoimmune diseases that suggested shared etiologic factors. Subsequently, the co-occurrence of different autoimmune diseases, including vitiligo, was reported by many investigators, particularly Schmidt, and key combinations of concomitant autoimmune diseases were later codified by Neufeld and Blizzard. Beginning with the vitiligo case series reported by Steve, numerous investigators have since documented prevalent co-occurrence of vitiligo with various other autoimmune diseases, particularly autoimmune thyroid disease (both Hashimoto disease and Graves disease), pernicious anemia, Addison disease, systemic lupus erythematosus, rheumatoid arthritis, adult-onset type 1 diabetes mellitus, and perhaps psoriasis. Of particular importance, these same vitiligo-associated autoimmune diseases also occur at increased frequency in first-degree relatives of vitiligo probands who do not themselves have vitiligo, indicating that these autoimmune diseases share at least some of their genetic underpinnings with vitiligo.
Early genetic marker studies
The earliest attempts to identify genetic markers associated with vitiligo began in the mid-1960s, assaying polymorphic blood proteins, such as the ABO and other blood group antigens ; secretor status ; and, later, serum alpha 1-antitrypsin and haptoglobin phenotypes, with no positive results. A decade later, numerous investigators reported association studies of vitiligo with human leukocyte antigen (HLA) types, which have also been associated with many other autoimmune diseases. Initial association studies of vitiligo and HLA yielded inconsistent and largely spurious findings due to testing different ethnic groups, inadequate statistical power, and inadequate correction for multiple-testing of many different HLA types. Nevertheless, Foley and colleagues correctly identified association of the HLA-DR4 class II serotype with vitiligo, borne out by subsequent studies, the first known genetic association for vitiligo. Importantly, HLA-DR4 is also strongly associated with several other autoimmune diseases.
A large number of additional HLA association studies of vitiligo were published subsequently, again with generally inconsistent findings. Nevertheless, Liu and colleagues conducted a careful meta-analysis of 11 previous studies of HLA class I serotypes and found robust association of vitiligo with HLA-A2 with odds ratio (OR) 2.07, a finding borne out by subsequent studies. Specific associations of vitiligo with the class I and class II gene regions of the major histocompatibility complex (MHC) were subsequently replicated and refined by detailed molecular genetic and genomewide association studies (GWASs), even to the point of identifying apparently causal genetic variation (see later discussion).
Non-major histocompatibility complex candidate gene association studies
The development of DNA technology in the late 1970s ushered in an era of testing candidate genes for association with a great many diseases, including vitiligo. Unfortunately, numerous retrospective studies have shown that well over 95% of published case-control genetic association studies represent false-positives, due to inadequate sample size and statistical fluctuation, genotyping errors, occult population stratification, inadequate correction for multiple-testing, and publication bias of positive results. As the result, this type of study is no longer considered appropriate for primary discovery of genetic association. Accordingly, of the approximately 70 genes for which association with vitiligo has been claimed based on such studies, this article discusses only those 2 non-MHC candidate gene associations that have received widespread independent confirmation, including by unbiased GWASs.
Kemp and colleagues reported the first vitiligo non-MHC candidate gene association with CTLA4 , which encodes a T-cell coreceptor involved in regulation of T-cell activation and which is associated with several of the other autoimmune diseases that are epidemiologically associated with vitiligo. In fact, CTLA4 association was strongest in vitiligo patients who also had other concomitant autoimmune diseases, a finding subsequently replicated by another study and meta-analysis. Association of CTLA4 with vitiligo has been variable among studies of different populations; however, at least in European-derived whites, it has been demonstrated by GWASs.
A second important non-MHC candidate gene association, also reported by Kemp, was with PTPN22 , encoding LYP protein tyrosine phosphatase, which likewise has been genetically associated with many different autoimmune diseases. Again, this association was replicated in most other studies of European-derived whites and by GWASs, but not in most other populations. Thus, along with HLA class II, CTLA4 and PTPN22 likely are 2 of the genes that underlie epidemiologic association of vitiligo with other autoimmune diseases, at least in European-derived whites.
Genomewide studies
Candidate gene analyses carry an intrinsic a priori bias by selection of genes for study. In contrast, genomewide analyses of polygenic, multifactorial diseases are, in principle, unbiased beyond the assumption that genetic factors play some role. There are 3 approaches to genomewide genetic analysis. Genomewide linkage analysis tests for cosegregation of polymorphic markers with disease within families with multiple affected relatives and across such families. Such families are uncommon, the genetic resolution of linkage is low, and the genetic analyses require several important assumptions that may not be correct. GWASs, the current gold standard, require large numbers of cases and controls but are reasonably powerful, can detect many genotyping errors, can provide fine-mapping, can detect population outliers and correct for population stratification, can appropriately account for multiple-testing, and require independent replication and a stringent genomewide significance criterion ( P <5 × 10 −8 ) to declare discovery. For reasons that are not clear, linkage and GWASs often do not detect the same genetic signals. Genomewide or exome DNA sequencing studies can be configured similarly to linkage or GWASs but are far more expensive and have not yet been applied to vitiligo.
Genetic Linkage Studies
Initial linkage studies of vitiligo were not genomewide, focusing on the MHC and other specific candidate regions of the genome, and will not be discussed here. The first genomewide linkage study of vitiligo was indirect. Nath and colleagues mapped a locus on chromosome 17p13 they called SLEV1 in a subset of lupus families who also had relatives with vitiligo. Spritz and colleagues subsequently confirmed the SLEV1 linkage signal by genomewide linkage analysis of vitiligo families in which various other autoimmune diseases also occurred. That group eventually fine-mapped and identified the corresponding gene as NLRP1 , which encodes an inflammasome regulatory protein.
In a unique large European-derived white kindred with near autosomal-dominant vitiligo, Spritz and colleagues used genomewide linkage to map a locus they termed Autoimmune Susceptibility 1 ( AIS1 ) at chromosome 1p31.3-p32.2. That group subsequently identified the corresponding gene as FOXD3 , encoding a key regulator of melanoblast differentiation. This vitiligo kindred was found to segregate a private sequence variant in the FOXD3 promoter that upregulated transcription in vitro, which would be expected to reduce melanoblast differentiation. Recently, Schunter and colleagues identified another FOXD3 promoter variant associated with vitiligo that also increases transcriptional activity. Spritz and colleagues also mapped 2 additional vitiligo linkage signals in European-derived white vitiligo families, AIS2 on chromosome 7 and AIS3 on chromosomes 8. Specific genes corresponding to AIS2 and AIS3 have not yet been identified.
In parallel linkage studies of Han Chinese vitiligo families, Zhang and colleagues identified 3 loci, AIS4 on chromosome 4q12-q21 and 2 unnamed loci on 6p21-p22 and 22q12. These investigators suggested that AIS4 might be PDGFRA , though this seems much less likely than KIT . The chromosome 6 locus may correspond to the MHC. Also, Ren and colleagues found that the chromosome 22 locus may correspond to XBP1 .
Genomewide Association Studies
The first GWAS of vitiligo was of a unique population isolate in Romania in which there is a very high prevalence of vitiligo and other autoimmune diseases. This study identified association with an SNP within SMOC2 on chromosome 6q27, in close vicinity to IDDM8 , a linkage and association signal for type 1 diabetes mellitus and rheumatoid arthritis.
The Spritz group has also carried out 3 successive GWASs of vitiligo of US-derived and European-derived whites. As shown in Table 1 , these analyses have identified confirmed associations of vitiligo with 48 distinct loci, altogether accounting for 22.5% of vitiligo heritability in European-derived whites, as well as several additional loci with suggestive significance. About half of the confirmed vitiligo loci encode immunoregulatory proteins, consistent with the autoimmune nature of vitiligo; several others encode regulators of apoptosis; and at least 6 encode either melanocyte components or regulators of melanocyte function. Of this last group, all have also been implicated in both normal pigmentary variation and risk of melanoma, and all show a remarkable inverse genetic relationship between vitiligo risk and melanoma risk, suggesting that vitiligo may result from dysregulation of a normal mechanism of immune surveillance for melanoma. Many of these proteins encoded by the confirmed vitiligo genes interact directly in functional biological pathways that are key to vitiligo pathogenesis ( Fig. 1 ), suggesting that most of the pathways involved in vitiligo susceptibility may have already been discovered.
| Chr. | Locus | Protein | Function |
|---|---|---|---|
| 1 | RERE | Arginine-glutamic acid dipeptide repeats | Regulator of apoptosis |
| 1 | PTPN22 | Protein tyrosine phosphatase, nonreceptor type 22 | Alters responsiveness of T-cell receptors |
| 1 | FASLG | FAS ligand | Regulator of immune apoptosis |
| 1 | PTPRC | Protein tyrosine phosphatase, receptor type C | Regulator of T- and B-cell antigen receptor signaling |
| 2 | PPP4R3B | Protein phosphatase 4 regulatory subunit 3B | Unknown |
| 2 | BCL2L11 ? | BCL2 like 11 | Regulator of apoptosis in thymocyte negative selection |
| 2 | IFIH1 | Interferon induced with helicase C domain 1 | Innate immune receptor |
| 2 | CTLA4 | Cytotoxic T-lymphocyte-associated protein 4 | T-lymphocyte checkpoint regulator |
| 2 | FARP2-STK25 | ? | ? |
| 3 | UBE2E2 | Ubiquitin-conjugating enzyme E2 E2 | Protein ubiquitination pathway; damage response |
| 3 | FOXP1 | Forkhead box protein P1 | Transcriptional regulator of B-cell development |
| 3 | CD80 | T-lymphocyte activation antigen CD80 | T-cell costimulatory signal |
| 3 | LPP | Lipoma-preferred partner | Unknown |
| 3 | FBXO45-NRROS | ? | ? |
| 4 | PPP3CA | Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform | T-lymphocyte calcium-dependent, calmodulin-stimulated protein phosphatase |
| 6 | IRF4 | Interferon regulatory factor 4 | Transcriptional activator in immune cells and melanocytes |
| 6 | SERPINB9 | Serpin B9 | Endogenous inhibitor of granzyme B |
| 6 | HLA-A | HLA class I histocompatibility antigen, A | Presents peptide antigens to the immune system |
| 6 | HLA-DRB1 / DQA1 | HLA class II histocompatibility antigens, DRB1 and DQA1 | Present peptide antigens to the immune system |
| 6 | BACH2 | BTB domain and CNC homolog 2 | Transcriptional activator, regulator of apoptosis |
| 6 | RNASET2-FGFR1OP-CCR6 | ? | ? |
| 7 | CPVL | Probable serine carboxypeptidase CPVL | Inflammatory protease; trims antigens for presentation |
| 8 | SLA | Src-like-adapter | Regulator of T-cell antigen receptor signaling |
| 9 | NEK6 | NIMA-related serine/threonine-protein kinase Nek6 | Regulator of apoptosis |
| 10 | IL2RA | Interleukin-2 receptor subunit alpha | IL2 receptor; regulates regulator T lymphocytes |
| 10 | ARID5B | AT-rich interactive domain-containing protein 5B | Transcriptional coactivator |
| 10 | ZMIZ1 | Zinc finger MIZ domain-containing protein 1 | Possible PIAS-family transcriptional or sumoylation regulator |
| 10 | CASP7 | Caspase-7 | Apoptosis executor protein |
| 11 | CD44 | CD44 antigen | Regulator of FOXP3 expression |
| 11 | PPP1R14B-PLCB3-BAD-GPR137-KCNK4-TEX40-ESRRA-TRMT112-PRDX5 | ? | ? |
| 11 | TYR | Tyrosinase | Melanocyte melanogenic enzyme; vitiligo autoantigen |
| 11 | Gene desert | ? | ? |
| 12 | PMEL | Premelanosome protein PMEL | Melanocyte melanosomal type I transmembrane glycoprotein |
| 12 | IKZF4 | Zinc finger protein Eos | Transcriptional repressor; regulates FOXP3 transcription in regulatory T lymphocytes |
| 12 | SH2B3 | SH2B adapter protein 3 | Links T-lymphocyte receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase |
| 13 | TNFSF11 | Tumor necrosis factor ligand superfamily member 11 | T-lymphocyte cytokine that binds to TNFRSF11A and TNFRSF11B |
| 14 | GZMB | Granzyme B | Apoptosis executioner protein of cytotoxic T lymphocytes |
| 15 | OCA2-HERC2 | Oculocutaneous albinism 2 | Melanocyte melanogenic protein; vitiligo autoantigen |
| 16 | MC1R | Melanocortin 1 receptor | Melanocyte melanogenic protein; vitiligo autoantigen |
| 17 | KAT2A-HSPB9-RAB5C | ? | ? |
| 18 | TNFRSF11A | Tumor necrosis factor receptor superfamily member 11A | Regulates interactions between T lymphocytes and dendritic cells |
| 19 | TICAM1 | TIR domain-containing adapter molecule 1 | TLR3/TLR4 adapter; mediates NF-kappa-B and interferon-regulatory factor (IRF) activation; induces apoptosis |
| 19 | SCAF1-IRF3-BCL2L12 | ? | ? |
| 20 | RALY- ASIP | Agouti signaling protein | Regulator of melanocytes via MC1R |
| 20 | PTPN1 | Tyrosine-protein phosphatase nonreceptor type 1 | Dephosphorylates JAK2 and TYK2 kinases; cellular response to interferon? |
| 21 | UBASH3A | Ubiquitin-associated and SH3 domain-containing protein A | Promotes accumulation of activated T-cell receptors on surface |
| 22 | C1QTNF6 | Complement C1q tumor necrosis factor-related protein 6 | Unknown |
| 22 | ZC3H7B-TEF | ? | ? |
| X | IL1RAPL1 | Interleukin-1 receptor accessory protein-like 1 | Unknown |
| X | CCDC22-FOXP3-GAGE | ? | FOXP3 regulates development and inhibitory function of regulatory T-lymphocytes |
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Quality of Life, Burden of Disease, Co-morbidities, and Systemic Effects in Vitiligo Patients
Skin Cancer Risk (Nonmelanoma Skin Cancers/Melanoma) in Vitiligo Patients
Phototherapy and Combination Therapies for Vitiligo
Surgical Therapies for Vitiligo
Vitiligo Pathogenesis and Emerging Treatments
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