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The CTLA-4 +49 A/G, CT60 A/G and PTPN22 1858 C/T polymorphisms and susceptibility to vitiligo: a meta-analysis

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Abstract

The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, CT60 A/G, and protein tyrosine phosphatase nonreceptor 22 (PTPN22) 1858 C/T polymorphisms confer susceptibility to vitiligo. A meta-analysis was conducted of the associations between the CTLA-4 +49 A/G, CT60 and PTPN22 1858 C/T polymorphisms and vitiligo using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 14 separate comparisons were considered in our meta-analysis consisting of 3,404 patients with vitiligo and 5,069 controls (nine studies with 1,252 cases and 2,152 controls for the CTLA-4 polymorphisms and five studies with 1,800 cases and 3,269 controls for the PTPN22 polymorphism). Meta-analysis showed no association between vitiligo and the CTLA-4 +49 A/G polymorphism in all study subjects (OR of the G allele = 1.186, 95 % CI = 0.893–1.575, p = 0.240) and in European (OR = 1.016, 95 % CI = 0.873–1.182, p = 0.838). However, meta-analysis of the CTLA-4 CT60 A/G polymorphism showed an association between vitiligo and the CTLA-4 CT60 G allele in all study subjects (OR = 1.267, 95 % CI = 1.110–1.447, p = 4.5 × 10−5) and in the European group (OR = 1.345, 95 % CI = 1.163–1.556, p = 6.3 × 10−6). Analysis using the recessive model and homozygote contrast showed the same pattern for the CTLA-4 CT60 G allele. Meta-analysis of the PTPN22 1858 C/T polymorphism showed an association between the PTPN22 T allele and vitiligo in all subjects (OR = 1.507, 95 % CI = 1.320–1.720, p < 1.0 × 10−8) and in European group (OR = 1.530, 95 % CI = 1.339–1.748, p < 1.0 × 10−8), but not in Asians (OR = 0.482, 95 % CI = 0.152–1.530, p = 0.216). Analysis using the recessive, dominant model, and homozygote contrast showed the same pattern for the PTPN22 T allele. This meta-analysis demonstrates that the CTLA-4 CT60 A/G polymorphism confers susceptibility to vitiligo in Europeans, but no association was found between the CTLA-4 +49 A/G polymorphism and vitiligo susceptibility. The PTPN22 C1858T polymorphism is associated with vitiligo susceptibility in European population.

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References

  1. Mollet I, Ongenae K, Naeyaert JM (2007) Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders. Dermatol Clin 25:363–371

    Article  PubMed  CAS  Google Scholar 

  2. Le Poole IC, Luiten RM (2008) Autoimmune etiology of generalized vitiligo. Curr Dir Autoimmun 10:227–243

    Article  PubMed  Google Scholar 

  3. Spritz RA (2008) The genetics of generalized vitiligo. Curr Dir Autoimmun 10:244–257

    Article  PubMed  CAS  Google Scholar 

  4. Greenwald RJ, Oosterwegel MA, van der Woude D, Kubal A, Mandelbrot DA, Boussiotis VA, Sharpe AH (2002) CTLA-4 regulates cell cycle progression during a primary immune response. Eur J Immunol 32:366–373

    Article  PubMed  CAS  Google Scholar 

  5. Lee YH, Harley JB, Nath SK (2005) CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis. Hum Genet 116:361–367

    Article  PubMed  CAS  Google Scholar 

  6. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RC, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Tuomilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Ronningen KS, Guja C, Ionescu-Tirgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SC (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511

    Article  PubMed  CAS  Google Scholar 

  7. Siminovitch KA (2004) PTPN22 and autoimmune disease. Nat Genet 36:1248–1249

    Article  PubMed  CAS  Google Scholar 

  8. Gregersen PK (2005) Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond. Immunol Rev 204:74–86

    Article  PubMed  CAS  Google Scholar 

  9. Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM (1999) Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 93:2013–2024

    PubMed  CAS  Google Scholar 

  10. Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338

    Article  PubMed  CAS  Google Scholar 

  11. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, Gregersen PK (2004) A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330–337

    Article  PubMed  CAS  Google Scholar 

  12. Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan AC (2004) PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303:685–689

    Article  PubMed  CAS  Google Scholar 

  13. Dwivedi M, Laddha NC, Imran M, Shah BJ, Begum R (2011) Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in isolated vitiligo: a genotype-phenotype correlation. Pigment Cell Melanoma Res 24:737–740

    Article  PubMed  CAS  Google Scholar 

  14. Deeba F, Syed R, Quareen J, Waheed MA, Jamil K, Rao H (2010) CTLA-4 A49G gene polymorphism is not associated with vitiligo in South Indian population. Indian J Dermatol 55:29–32

    Article  PubMed  Google Scholar 

  15. Birlea SA, Laberge GS, Procopciuc LM, Fain PR, Spritz RA (2009) CTLA4 and generalized vitiligo: two genetic association studies and a meta-analysis of published data. Pigment Cell Melanoma Res 22:230–234

    Article  PubMed  Google Scholar 

  16. Pehlivan S, Ozkinay F, Alper S, Onay H, Yuksel E, Pehlivan M, Ozkinay C (2009) Association between IL4 (-590), ACE (I)/(D), CCR5 (Delta32), CTLA4 (+49) and IL1-RN (VNTR in intron 2) gene polymorphisms and vitiligo. Eur J Dermatol 19:126–128

    PubMed  CAS  Google Scholar 

  17. Blomhoff A, Kemp EH, Gawkrodger DJ, Weetman AP, Husebye ES, Akselsen HE, Lie BA, Undlien DE (2005) CTLA4 polymorphisms are associated with vitiligo, in patients with concomitant autoimmune diseases. Pigment Cell Res 18:55–58

    Article  PubMed  CAS  Google Scholar 

  18. Itirli G, Pehlivan M, Alper S, Yuksel SE, Onay H, Ozkinay F, Pehlivan S (2005) Exon-3 polymorphism of CTLA-4 gene in Turkish patients with vitiligo. J Dermatol Sci 38:225–227

    Article  PubMed  CAS  Google Scholar 

  19. Kemp EH, Ajjan RA, Waterman EA, Gawkrodger DJ, Cork MJ, Watson PF, Weetman AP (1999) Analysis of a microsatellite polymorphism of the cytotoxic T-lymphocyte antigen-4 gene in patients with vitiligo. Br J Dermatol 140:73–78

    Article  PubMed  CAS  Google Scholar 

  20. Alkhateeb A, Qarqaz F, Al-Sabah J, Al Rashaideh T (2010) Clinical characteristics and PTPN22 1858C/T variant analysis in Jordanian Arab vitiligo patients. Mol Diagn Ther 14:179–184

    Article  PubMed  CAS  Google Scholar 

  21. Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ, Mailloux CM, Sufit AJ, Hutton SM, Amadi-Myers A, Bennett DC, Wallace MR, McCormack WT, Kemp EH, Gawkrodger DJ, Weetman AP, Picardo M, Leone G, Taieb A, Jouary T, Ezzedine K, van Geel N, Lambert J, Overbeck A, Spritz RA (2010) Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med 362:1686–1697

    Article  PubMed  CAS  Google Scholar 

  22. Laberge GS, Birlea SA, Fain PR, Spritz RA (2008) The PTPN22-1858C>T (R620W) functional polymorphism is associated with generalized vitiligo in the Romanian population. Pigment Cell Melanoma Res 21:206–208

    Article  PubMed  CAS  Google Scholar 

  23. Laddha NC, Dwivedi M, Shajil EM, Prajapati H, Marfatia YS, Begum R (2008) Association of PTPN22 1858C/T polymorphism with vitiligo susceptibility in Gujarat population. J Dermatol Sci 49:260–262

    Article  PubMed  CAS  Google Scholar 

  24. Canton I, Akhtar S, Gavalas NG, Gawkrodger DJ, Blomhoff A, Watson PF, Weetman AP, Kemp EH (2005) A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo. Genes Immun 6:584–587

    Article  PubMed  CAS  Google Scholar 

  25. Shin MK, Im SH, Park HJ, Kim SK, Yim SV, Chung JH, Lee MH (2011) Association study between polymorphisms of CD28, CTLA4 and ICOS and non-segmental vitiligo in a Korean population. Exp Ther Med 2:1145–1149

    PubMed  CAS  Google Scholar 

  26. Nath SK, Harley JB, Lee YH (2005) Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum Genet 118:225–234

    Article  PubMed  CAS  Google Scholar 

  27. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG (2006) Association of TNF-alpha -308 G/A polymorphism with responsiveness to TNF-alpha-blockers in rheumatoid arthritis: a meta-analysis. Rheumatol Int 27:157–161

    Article  PubMed  CAS  Google Scholar 

  28. Lee YH, Song GG (2011) Efficacy and safety of monthly 150 mg oral ibandronate in women with postmenopausal osteoporosis: a systematic review and meta-analysis of randomized controlled trials. Korean J Intern Med 26:340–347

    Article  PubMed  CAS  Google Scholar 

  29. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed  CAS  Google Scholar 

  30. Duval S, Tweedie R (2000) Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56:455–463

    Article  PubMed  CAS  Google Scholar 

  31. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  32. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  PubMed  CAS  Google Scholar 

  33. LaBerge GS, Bennett DC, Fain PR, Spritz RA (2008) PTPN22 is genetically associated with risk of generalized vitiligo, but CTLA4 is not. J Invest Dermatol 128:1757–1762

    Article  PubMed  CAS  Google Scholar 

  34. Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA Jr, Ke X, Gray GS et al (1995) CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A 92:811–815

    Article  PubMed  CAS  Google Scholar 

  35. Lee YH, Bae SC, Choi SJ, Ji JD, Song GG (2012) Association between the CTLA-4 +49 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep 39:5599–5605

    Article  PubMed  CAS  Google Scholar 

  36. Lee YH, Choi SJ, Ji JD, Song GG (2012) CTLA-4 and TNF-alpha promoter-308 A/G polymorphisms and ANCA-associated vasculitis susceptibility: a meta-analysis. Mol Biol Rep 39:319–326

    Article  PubMed  CAS  Google Scholar 

  37. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK, Harley JB (2007) The PTPN22 C1858T functional polymorphism and autoimmune diseases: a meta-analysis. Rheumatology (Oxford) 46:49–56

    Article  CAS  Google Scholar 

  38. Gregersen PK, Lee HS, Batliwalla F, Begovich AB (2006) PTPN22: setting thresholds for autoimmunity. Semin Immunol 18:214–223

    Article  PubMed  CAS  Google Scholar 

  39. Lee HS, Korman BD, Le JM, Kastner DL, Remmers EF, Gregersen PK, Bae SC (2009) Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum 60:364–371

    Article  PubMed  CAS  Google Scholar 

  40. Ban Y, Tozaki T, Taniyama M, Tomita M (2005) The codon 620 single nucleotide polymorphism of the protein tyrosine phosphatase-22 gene does not contribute to autoimmune thyroid disease susceptibility in the Japanese. Thyroid 15:1115–1118

    Article  PubMed  CAS  Google Scholar 

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This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Correspondence to Young Ho Lee.

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Song, G.G., Kim, JH. & Lee, Y.H. The CTLA-4 +49 A/G, CT60 A/G and PTPN22 1858 C/T polymorphisms and susceptibility to vitiligo: a meta-analysis. Mol Biol Rep 40, 2985–2993 (2013). https://doi.org/10.1007/s11033-012-2370-9

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