Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Jin, Ying; Andersen, Genevieve; Yorgov, Daniel; Ferrara, Tracey M.; Ben, Songtao; Brownson, Kelly M.; Holland, Paulene J.; Birlea, Stanca A.; Siebert, Janet; Hartmann, Anke; Lienert, Anne; Geel, Nanja van; Lambert, Jo; Luiten, Rosalie M.; Wolkerstorfer, Albert; Veen, J.P.W. van der; Bennett, Dorothy C.; Taı̈eb, Alain; Ezzedine, Khaled; Kemp, E. Helen; Gawkrodger, David J.; Weetman, Anthony P.; Kõks, Sulev; Prans, Ele; Kingo, Külli; Karelson, Maire; Wallace, Margaret R.; McCormack, Wayne T.; Overbeck, Andreas; Moretti, Silvia; Colucci, Roberta; Picardo, Mauro; Silverberg, Nanette B.; Olsson, Mats Joakim Robert; Valle, Yan; Коробко, И. В.; Böhm, Markus; Lim, Henry W.; Hamzavi, Iltefat; Zhou, Li; Mi, Qing Sheng; Fain, Pamela R.; Santorico, Stephanie A.; Spritz, Richard A.

doi:10.1038/ng.3680

Cited by 245 publications

(222 citation statements)

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“…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 [65]. About half of the confirmed vitiligo loci encode immunoregulatory proteins, consistent with the autoimmune nature of vitiligo, a number of others encode regulators of apoptosis, and at least six encode either melanocyte components or regulators of melanocyte function.…”

Section: Genomewide Studiesmentioning

confidence: 83%

“…The Spritz group has also carried out three successive GWAS of vitiligo of USA and European-derived whites [62–65]. 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 [65].…”

Section: Genomewide Studiesmentioning

confidence: 99%

“…About half of the confirmed vitiligo loci encode immunoregulatory proteins, consistent with the autoimmune nature of vitiligo, a number of others encode regulators of apoptosis, and at least six 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 [62,63,65], suggesting that vitiligo may result from dysregulation of a normal mechanism of immune surveillance for melanoma [66,67]. Many of these proteins encoded by the confirmed vitiligo genes interact directly in functional biological pathways that are key to vitiligo pathogenesis (Figure 1), suggesting that a majority of the pathways involved in vitiligo susceptibility may have already been discovered.…”

Section: Genomewide Studiesmentioning

confidence: 99%

“…Of these associations in Chinese, only that in the RNASET2-FGFR1OP-CCR6 region corresponds to an association detected in Caucasian patients [63]. Indeed, while MHC class I and class II region associations were detected in Caucasians [62,65,68,69,71] and Chinese [76], the specific underlying associations appear to be somewhat different. This is surprising, as a GWAS of vitiligo in Japanese [79] detected an MHC class I association with HLA-A*02:01 that appears identical to that in European-derived whites, while an immunocentric GWAS of vitiligo in Asian Indian and Pakistani patients detected an MHC class II association that similar to that European-derived whites [80], though more detailed MHC analysis in Indians [81] found class II association that was the same as in Chinese [76].…”

Section: Genomewide Studiesmentioning

confidence: 99%

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Genetics of Vitiligo

Spritz¹,

Andersen²

2017

Dermatologic Clinics

141

122

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Synopsis Vitiligo is “complex disorder” (also termed polygenic and multifactorial), reflecting simultaneous contributions of multiple genetic risk factors and environmental triggers. Large-scale genome-wide 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. A large fraction of these genes encode proteins involved in immune regulation, a number of others play roles in cellular apoptosis, and still others are involved in regulating functions of melanocytes. For this last group, there appears to be an opposite relationship between susceptibility to vitiligo and susceptibility to melanoma, suggesting that vitiligo may engage a normal mechanism of immune surveillance for melanoma. While 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.

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Section: Genomewide Studiesmentioning

confidence: 83%

Section: Genomewide Studiesmentioning

confidence: 99%

Section: Genomewide Studiesmentioning

confidence: 99%

Section: Genomewide Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Genetics of Vitiligo

Spritz¹,

Andersen²

2017

Dermatologic Clinics

141

122

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“…Genotyping of PSMB8 intron 6 rs2071464 SNP by PCR-RFLP using Hha I and subsequent sequencing results revealed that there is C>T nucleotide change instead of previously reported G>T change, which falls in the Hha I recognition/restriction site and was imputed to PSMB8 rs2071464 SNP [12,19,34,35]. The observed genotype frequencies of PSMB8 rs2071464 SNP among the controls were in accordance ( p = 0.071) whereas, genotype frequencies among the patients were deviated ( p = 0.001) from HWE.…”

Section: Resultsmentioning

confidence: 99%

A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat

et al. 2017

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BackgroundAutoimmunity has been implicated in the destruction of melanocytes from vitiligo skin. Major histocompatibility complex (MHC) class-II linked genes proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1), involved in antigen processing and presentation have been reported to be associated with several autoimmune diseases including vitiligo.ObjectivesTo explore PSMB8 rs2071464 and TAP1 rs1135216 single nucleotide polymorphisms and to estimate the expression of PSMB8 and TAP1 in patients with vitiligo and unaffected controls from Gujarat.MethodsPSMB8 rs2071464 polymorphism was genotyped using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and TAP1 rs1135216 polymorphism was genotyped by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 378 patients with vitiligo and 509 controls. Transcript levels of PSMB8 and TAP1 were measured in the PBMCs of 91 patients and 96 controls by using qPCR. Protein levels of PSMB8 were also determined by Western blot analysis.ResultsThe frequency of ‘TT’ genotype of PSMB8 polymorphism was significantly lowered in patients with generalized and active vitiligo (p = 0.019 and p = 0.005) as compared to controls suggesting its association with the activity of the disease. However, TAP1 polymorphism was not associated with vitiligo susceptibility. A significant decrease in expression of PSMB8 at both transcript level (p = 0.002) as well as protein level (p = 0.0460) was observed in vitiligo patients as compared to controls. No significant difference was observed between patients and controls for TAP1 transcripts (p = 0.553). Interestingly, individuals with the susceptible CC genotype of PSMB8 polymorphism showed significantly reduced PSMB8 transcript level as compared to that of CT and TT genotypes (p = 0.009 and p = 0.003 respectively).ConclusionsPSMB8 rs2071464 was associated with generalized and active vitiligo from Gujarat whereas TAP1 rs1135216 showed no association. The down-regulation of PSMB8 in patients with risk genotype ‘CC’ advocates the vital role of PSMB8 in the autoimmune basis of vitiligo.

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Genetics of Vitiligo

Roberts¹,

Spritz²

2018

Encyclopedia of Life Sciences

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Vitiligo is an autoimmune disease that results in destruction of skin melanocytes and patches of white skin and hair. Family studies of vitiligo demonstrated that a strong, but complex genetic component underlies disease risk and that vitiligo often occurs with other autoimmune diseases, suggesting shared autoimmune susceptibility. Genome‐wide linkage and association studies have identified over 50 vitiligo susceptibility loci, with most loci harbouring genes involved in immune regulation, apoptosis or melanocyte function. The identified loci fit together in a model of melanocyte‐directed autoimmunity, and many loci are shared with other autoimmune diseases. Surprisingly, some genetic vitiligo susceptibility alleles are inversely associated with melanoma, suggesting that vitiligo represents enhanced immune surveillance against melanoma. Genetic studies of vitiligo have greatly advanced understanding of vitiligo pathobiology and may additionally provide insights into melanoma and other autoimmune disease. Key Concepts Vitiligo is a multifactorial disease, in which multiple genetic and environmental factors contribute to disease risk. The genetic architecture of vitiligo is typically (and perhaps always) polygenic, with a strong genetic component underlying disease risk. Over 50 genetic loci have been associated with vitiligo risk; these loci fit together in a model of melanocyte‐directed autoimmune pathobiology. Most variants associated with vitiligo are in noncoding regions and presumably affect gene regulation. Nevertheless, some associated coding variants and physical interaction among proteins encoded by some vitiligo susceptibility genes provide special insights into pathogenesis. Vitiligo shares many genetic risk factors with other autoimmune diseases with which it is epidemiologically associated, supporting a component of common autoimmune pathogenesis.

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Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

Cited by 245 publications

References 71 publications

Genetics of Vitiligo

Genetics of Vitiligo

A case-control study on association of proteasome subunit beta 8 (PSMB8) and transporter associated with antigen processing 1 (TAP1) polymorphisms and their transcript levels in vitiligo from Gujarat

Genetics of Vitiligo

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