FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2029781663> ?p ?o ?g. }

• W2029781663 endingPage "1733" @default.
• W2029781663 startingPage "1730" @default.
• W2029781663 abstract "European-derived whites generalized vitiligo genome-wide association study major histocompatibility complex oculocutaneous albinism type 1 odds ratio single-nucleotide polymorphism tyrosinase (gene or protein) TO THE EDITOR Generalized vitiligo (GV) is a common autoimmune disease resulting from the destruction of melanocytes in the involved areas, epidemiologically associated with elevated prevalence of certain other autoimmune diseases (Picardo and Taïeb, 2010Picardo M. Taïeb A. Vitiligo. Springer, New York2010Crossref Scopus (42) Google Scholar). In a recent genome-wide association study (GWAS) of GV, carried out in European-derived whites (EUR), we identified 16 loci that contribute to GV risk (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.New 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; Birlea et al., 2011Birlea 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). Within the major histocompatibility complex (MHC), a major GV association signal localized to HLA-A, in the class I gene region. Outside the MHC, the strongest GV association was with TYR, which encodes tyrosinase (TYR). At HLA-A, the most highly associated single-nucleotide polymorphism (SNP) was rs12206499 (P=1.24 × 10−19, odds ratio (OR)=1.58), which tags HLA-A*02 (r2=0.964, D′=1.0) in the EUR population (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.New Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar). At TYR, the strongest association was with rs1393350 (P=3.24 × 10−13, OR=0.65), which is in linkage disequilibrium (r2=0.79. D′=1) with a common non-synonymous TYR variant, R402Q (rs1126809; Giebel et al., 1991Giebel L.B. Strunk K.M. Spritz R.A. Organization and nucleotide sequences of the human tyrosinase gene and a truncated tyrosinase-related segment.Genomics. 1991; 9: 435-445Crossref PubMed Scopus (128) Google Scholar). TYR is the major GV autoimmune antigen (Song et al., 1994Song Y.H. Connor E. Li Y. et al.The role of tyrosinase in autoimmune vitiligo.Lancet. 1994; 344: 1049-1052Abstract PubMed Scopus (172) Google Scholar), and TYR peptide antigens are predominantly presented on the melanocyte surface by HLA-A*02:01 (Brichard et al., 1993Brichard V. Van Pel A. Wölfel T. et al.The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas.J Exp Med. 1993; 178: 489-495Crossref PubMed Scopus (912) Google Scholar). The TYR R402Q substitution results in a temperature-sensitive tyrosinase TYR polypeptide (Tripathi et al., 1991Tripathi R.K. Giebel L.B. Strunk K.M. et al.A polymorphism of the human tyrosinase gene is associated with temperature-sensitive enzymatic activity.Gene Expr. 1991; 1: 103-110PubMed Google Scholar) that is retained in the endoplasmic reticulum, is hypoglycosylated, and is preferentially degraded (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). We therefore suggested that TYR R402Q might protect from GV by reducing the availability of TYR peptide for antigen presentation by HLA*02:01 (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.New Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar). To specifically define the HLA-A subtype associated with GV, we performed next-generation DNA re-sequencing of HLA-A exons 2, 3, and 4, which contain the sequence variations that define HLA-A subtypes (http://www.ebi.ac.uk/imgt/hla/), in 20 unrelated EUR GV patients. To maximize information, each patient was selected on the basis of homozygosity for rs12206499-G, which tags the GV-associated HLA-A*02 type (r2=0.964, D′=1.0) in the EUR population (Jin et al., 2010aJin Y. Birlea S.A. Fain P.R. et al.Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.New Engl J Med. 2010; 362: 1686-1697Crossref PubMed Scopus (291) Google Scholar). As shown in Supplementary Table S1 online, of the 20 patients sequenced, 18 were homozygous HLA-A*02:01/*02:01, 1 was heterozygous HLA-A*02:01/*02:20:01, and 1 was HLA-A*02:06:01/*02:30. (The allelic typing system does not distinguish between the common HLA-A*02:01:01:01 allele and the very rare HLA-A*02:01:01:02L allele; to be conservative, here we represent these alleles using the standard four-digit nomenclature, HLA-A*02:01). This distribution of HLA-A*02 subtypes is similar to that in EUR control populations (http://www.ncbi.nlm.nih.gov/gv/mhc/main.cgi?cmd=init; http://www.allelefrequencies.net/), indicating that the predominant HLA-A*02 GV risk subtype is HLA-A*02:01. Download .pdf (.73 MB) Help with pdf files Supplementary Information To specifically identify TYR gene variants associated with GV, we carried out next-generation re-sequencing of 10.4kb across the TYR locus, including 2.4kb of promoter, the five exons and adjacent intron sequences, and 3.2kb downstream, in 114 unrelated EUR GV patients. As shown in Supplementary Table S2 online, we identified 31 SNPs, with no indels or other rearrangements. Bioinformatic analyses predicted that only three of these are functionally significant. One, rs61754388 (T373K), is a known oculocutaneous albinism type 1 (OCA1) mutation (Spritz et al., 1990Spritz R.A. Strunk K.M. Giebel L.B. et al.Detection of mutations in the tyrosinase gene in a patient with type IA oculocutaneous albinism.N Engl J Med. 1990; 322: 1724-1728Crossref PubMed Scopus (69) Google Scholar), seen in a single heterozygote, consistent with the expected carrier frequency of OCA1. The other two, rs1042602 (S192Y) and rs1126809 (R402Q), are common non-synonymous polymorphisms (Giebel and Spritz, 1990Giebel L.B. Spritz R.A. RFLP for MboI in the human tyrosinase (TYR) gene detected by PCR.Nucleic Acids Res. 1990; 18: 3103Crossref PubMed Scopus (41) Google Scholar; Giebel et al., 1991Giebel L.B. Strunk K.M. Spritz R.A. Organization and nucleotide sequences of the human tyrosinase gene and a truncated tyrosinase-related segment.Genomics. 1991; 9: 435-445Crossref PubMed Scopus (128) Google Scholar) that occur almost exclusively in EUR populations (http://www.ncbi.nlm.nih.gov/projects/SNP/). In the GWAS, imputed rs1126809 genotypes demonstrated strongly protective association of the variant A allele with GV (P=1.36 × 10−14, OR=0.65), whereas rs1042602 showed no association (P=0.611, OR=0.98). However, when both variants were considered simultaneously by logistic regression (Table 1A), rs1042602 was also significantly associated with GV (P=1.23 × 10−4); when analyzed individually, association of rs1042602 was masked because its protective allele A is in linkage disequilibrium with the risk allele G of rs1126809; r2 between the two SNPs is 0.15. Furthermore, haplotype analysis of rs1042602 and rs1126809 (Table 1B) showed that, compared with the ancestral reference haplotype C-G, the other three rs1042602-rs1126809 variant haplotypes define a protective haplotypic series, the double-variant A-A haplotype reducing GV risk 3.7-fold: A-G, OR 0.83; C-A, OR 0.61; and A-A, OR 0.27. The overall P-value for a model including the additive effects of each haplotype is 3.76 × 10−17 (including dominance effects in the model did not improve significance; Supplementary Table S3 online).Table 1Association of GV with non-synonymous TYR rs1042602 and rs1126809 variants and haplotypesSNPMinor alleleFrequency in casesFrequency in controlsNominal P-valueORP-value conditional on rs1126809P-value conditional on rs1042602A. Association with individual variantsrs1042602 (S192Y)A0.360.370.6110.981.23 × 10−4rs1126809 (R402Q)A0.210.291.36 × 10−140.651.04 × 10−17HaplotypeC-GA-GC-AA-AOverallB. Association with rs1042602-rs1126809 haplotypesFrequency0.390.350.250.01OR1.01The ancestral C-G haplotype was used as the reference, with OR defined as 1.0, and thus was not included the model. The ORs and P-values were calculated with the additive effects of haplotypes A-A, C-A, and A-G included in the same model.0.830.610.27P6.74 × 10−42.02 × 10−155.82 × 10−43.76 × 10−17Abbreviations: GV, generalized vitiligo; OR, odds ratio.1 The ancestral C-G haplotype was used as the reference, with OR defined as 1.0, and thus was not included the model.The ORs and P-values were calculated with the additive effects of haplotypes A-A, C-A, and A-G included in the same model. Open table in a new tab Abbreviations: GV, generalized vitiligo; OR, odds ratio. To assess possible contributions of other deleterious TYR variants to GV risk, we imputed SNP genotypes across 334kb of the TYR region of 11q14.3 based on 1000 Genome Project EUR data (http://www.1000genomes.org/data). While many SNPs (MAF>0.01) showed significant association with GV (Supplementary Table S4 online), logistic regression analysis showed that none remained significant after conditioning on rs1126809 or on rs1126809 plus rs1042602. Together with the absence of rare predicted deleterious variants observed by sequencing, this suggests that rs1126809 and rs1042602 likely account for most genetic association of GV with common TYR variants in the EUR population. Together, HLA-A*02:01 and TYR mediate one of the principal pathways of immune recognition of melanocytes by autoreactive CTL. One of the major melanocyte autoantigens is TYR, of which degradation peptides are presented as antigenic epitopes on the melanocyte surface, principally by HLA-A*02:01 (Brichard et al., 1993Brichard V. Van Pel A. Wölfel T. et al.The tyrosinase gene codes for an antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas.J Exp Med. 1993; 178: 489-495Crossref PubMed Scopus (912) Google Scholar), consistent with our sequencing results identifying HLA-A*02:01 as the predominant GV-associated HLA-A*02 subtype. The best-studied HLA-A*02-restricted TYR antigenic epitope is TYR369-377 (YMDGTMSQV), of which residue D371 derives from deamidation of N371 on removal of an N-linked oligosaccharide (Skipper et al., 1996Skipper J.C. 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), a modification required for efficient presentation by HLA-A*02:01 (Skipper et al., 1996Skipper J.C. 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, N-glycosylation of R402Q TYR is greatly reduced at 37°C (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), likely preventing the subsequent N-deglycosylation-dependent N371D modification, reducing antigenic presentation by HLA-A*02:01, reducing target-cell recognition by melanocyte-specific CTL, and thus protecting from GV. Although not yet studied experimentally, the biological consequences of the TYR S192Y substitution may be analogous to those of R402Q. The TYR S192Y and R402Q variants occur essentially only in EUR-derived populations. Similarly, HLA-A*02:01 is common in EUR-derived populations, but is far less frequent in Asia, perhaps explaining why association signals at neither HLA-A nor TYR were observed in a GWAS of GV 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). Nevertheless, TYR may have an important role in the pathogenesis of GV in many or all populations, but the lack of functional TYR variation outside of EUR populations may preclude the ability to detect genetic association with GV in non-EUR populations. The TYR R402Q variant, while protective for GV, is conversely associated with increased risk of malignant melanoma (reviewed in Spritz, 2010Spritz R.A. The genetics of generalized vitiligo and an inverse relationship with malignant melanoma.Genome Med. 2010; 2: 78Crossref PubMed Scopus (70) Google Scholar). Moreover, HLA-A*02:01, although associated with increased risk of GV, is associated with relatively good response to melanoma immunotherapy (Mitchell et al., 1992Mitchell M.S. Hrel W. Groshen S. Association of HLA phenotype with response to active specific immunotherapy of melanoma.J Clin Oncol. 1992; 10: 1158-1164PubMed Google Scholar), which depends on presentation and recognition of melanocyte antigens. Together, the opposite genetic influences of HLA-A*02:01 and TYR with respect to GV versus malignant melanoma suggest that both findings may relate to a common underlying mechanism, in which TYR S192Y and R402Q haplotypes modulate the amount of TYR presentation by HLA-A*02:01, thereby modulating recognition of melanocytes by autoreactive CTL. Constitutive low-level autoimmunity may be part of a normal mechanism of immune surveillance to detect and destroy neoplastic melanocytes, whereas in GV dysregulation of this mechanism might lead to immune targeting and destruction of normal melanocytes (Spritz, 2010Spritz R.A. The genetics of generalized vitiligo and an inverse relationship with malignant melanoma.Genome Med. 2010; 2: 78Crossref PubMed Scopus (70) Google Scholar). This may have significant implications for the utility of suppressing the HLA-A-TYR pathway as a treatment for GV, as doing so might thus increase the risk of malignant melanoma. All participants provided written, informed consent to participate in the study, which was approved by the Colorado Multiple Institutional Review Board (COMIRB) at the University of Colorado Denver. The study complied with Declaration of Helsinki principles. This work was supported by grants AR45584, AR056292, and AR056292-02S1 from the US National Institutes of Health. We thank Cassidy Punt and Marc Strong for laboratory assistance, Tamim Shaikh for critical reading of the manuscript, and the many vitiligo patients and family members who participated in this study. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid" @default.
• W2029781663 created "2016-06-24" @default.
• W2029781663 creator A5016200361 @default.
• W2029781663 creator A5016431964 @default.
• W2029781663 creator A5022261999 @default.
• W2029781663 creator A5029624928 @default.
• W2029781663 creator A5030617710 @default.
• W2029781663 creator A5060087427 @default.
• W2029781663 creator A5079793510 @default.
• W2029781663 creator A5090028463 @default.
• W2029781663 date "2012-06-01" @default.
• W2029781663 modified "2023-10-12" @default.
• W2029781663 title "Next-Generation DNA Re-Sequencing Identifies Common Variants of TYR and HLA-A that Modulate the Risk of Generalized Vitiligo via Antigen Presentation" @default.
• W2029781663 cites W1831933605 @default.
• W2029781663 cites W2033667847 @default.
• W2029781663 cites W2047491064 @default.
• W2029781663 cites W2060325216 @default.
• W2029781663 cites W2088541521 @default.
• W2029781663 cites W2088970282 @default.
• W2029781663 cites W2114657480 @default.
• W2029781663 cites W2127996469 @default.
• W2029781663 cites W2129310091 @default.
• W2029781663 cites W2141665982 @default.
• W2029781663 cites W2169840688 @default.
• W2029781663 cites W2341021278 @default.
• W2029781663 cites W4236309979 @default.
• W2029781663 doi "https://doi.org/10.1038/jid.2012.37" @default.
• W2029781663 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3513338" @default.
• W2029781663 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22402439" @default.
• W2029781663 hasPublicationYear "2012" @default.
• W2029781663 type Work @default.
• W2029781663 sameAs 2029781663 @default.
• W2029781663 citedByCount "56" @default.
• W2029781663 countsByYear W20297816632012 @default.
• W2029781663 countsByYear W20297816632013 @default.
• W2029781663 countsByYear W20297816632014 @default.
• W2029781663 countsByYear W20297816632015 @default.
• W2029781663 countsByYear W20297816632016 @default.
• W2029781663 countsByYear W20297816632017 @default.
• W2029781663 countsByYear W20297816632018 @default.
• W2029781663 countsByYear W20297816632019 @default.
• W2029781663 countsByYear W20297816632020 @default.
• W2029781663 countsByYear W20297816632021 @default.
• W2029781663 countsByYear W20297816632022 @default.
• W2029781663 countsByYear W20297816632023 @default.
• W2029781663 crossrefType "journal-article" @default.
• W2029781663 hasAuthorship W2029781663A5016200361 @default.
• W2029781663 hasAuthorship W2029781663A5016431964 @default.
• W2029781663 hasAuthorship W2029781663A5022261999 @default.
• W2029781663 hasAuthorship W2029781663A5029624928 @default.
• W2029781663 hasAuthorship W2029781663A5030617710 @default.
• W2029781663 hasAuthorship W2029781663A5060087427 @default.
• W2029781663 hasAuthorship W2029781663A5079793510 @default.
• W2029781663 hasAuthorship W2029781663A5090028463 @default.
• W2029781663 hasBestOaLocation W20297816631 @default.
• W2029781663 hasConcept C126838900 @default.
• W2029781663 hasConcept C147483822 @default.
• W2029781663 hasConcept C188280979 @default.
• W2029781663 hasConcept C203014093 @default.
• W2029781663 hasConcept C2776090121 @default.
• W2029781663 hasConcept C2777601897 @default.
• W2029781663 hasConcept C2779980618 @default.
• W2029781663 hasConcept C51679486 @default.
• W2029781663 hasConcept C54355233 @default.
• W2029781663 hasConcept C552990157 @default.
• W2029781663 hasConcept C70721500 @default.
• W2029781663 hasConcept C71924100 @default.
• W2029781663 hasConcept C83464605 @default.
• W2029781663 hasConcept C86803240 @default.
• W2029781663 hasConcept C8891405 @default.
• W2029781663 hasConceptScore W2029781663C126838900 @default.
• W2029781663 hasConceptScore W2029781663C147483822 @default.
• W2029781663 hasConceptScore W2029781663C188280979 @default.
• W2029781663 hasConceptScore W2029781663C203014093 @default.
• W2029781663 hasConceptScore W2029781663C2776090121 @default.
• W2029781663 hasConceptScore W2029781663C2777601897 @default.
• W2029781663 hasConceptScore W2029781663C2779980618 @default.
• W2029781663 hasConceptScore W2029781663C51679486 @default.
• W2029781663 hasConceptScore W2029781663C54355233 @default.
• W2029781663 hasConceptScore W2029781663C552990157 @default.
• W2029781663 hasConceptScore W2029781663C70721500 @default.
• W2029781663 hasConceptScore W2029781663C71924100 @default.
• W2029781663 hasConceptScore W2029781663C83464605 @default.
• W2029781663 hasConceptScore W2029781663C86803240 @default.
• W2029781663 hasConceptScore W2029781663C8891405 @default.
• W2029781663 hasIssue "6" @default.
• W2029781663 hasLocation W20297816631 @default.
• W2029781663 hasLocation W20297816632 @default.
• W2029781663 hasLocation W20297816633 @default.
• W2029781663 hasLocation W20297816634 @default.
• W2029781663 hasOpenAccess W2029781663 @default.
• W2029781663 hasPrimaryLocation W20297816631 @default.
• W2029781663 hasRelatedWork W1970734801 @default.
• W2029781663 hasRelatedWork W2083264940 @default.
• W2029781663 hasRelatedWork W2122536851 @default.
• W2029781663 hasRelatedWork W2328367421 @default.
• W2029781663 hasRelatedWork W2361302679 @default.
• W2029781663 hasRelatedWork W2376842615 @default.

• next