Skip to main content
SpringerLink
Log in

The associations between PD-1, CTLA-4 gene polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis and systemic review

  • Original Article - Genes and Disease
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

Previous surveys had evaluated the effects of the PD-1, CTLA-4 gene polymorphisms on susceptibility to ankylosing spondylitis (AS), but the results remained controversial. To briefly examine these consequences, a comprehensive meta-analysis was conducted to estimate the relationships between PD-1 rs11568821, rs2227982, rs2227981, CTLA-4 +49 A/G and −318 C/T polymorphisms and AS risk. The available articles dated to December 2014 were searched in the PUBMED, MEDLINE and EMBASE databases. The data of the genotypes and/or alleles for the PD-1 rs11568821, rs2227982, rs2227981, CTLA-4 +49 A/G and −318 C/T polymorphisms in the AS and control subjects were extracted, and statistical analysis was conducted by STATA 11.2 software. Summary odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) were calculated to determine the strength of associations with fixed-effects or random-effects models. A total of eight published studies were finally involved in this meta-analysis. Meta-analysis of PD-1 rs2227982 polymorphism under the T allele versus C allele (OR 1.744, 95 % CI 1.477–2.059, P < 0.0001), TT+TC versus CC (OR 2.292, 95 % CI 1.654–3.175, P < 0.0001), TT versus CC (OR 1.883, 95 % CI 1.299–2.729, P = 0.001) revealed a significant association with AS. Our meta-analysis demonstrated that the rs2227982 polymorphism in the PD-1 gene might contribute to AS susceptibility. However, further studies with large sample sizes and among different ethnicity populations should be required to confirm this association.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Brown MA, Wordsworth BP, Reveille JD (2002) Genetics of ankylosing spondylitis. Clin Exp Rheumatol 20:S43–S49

    PubMed  CAS  Google Scholar 

  2. Ng SC, Liao Z, Yu DT et al (2007) Epidemiology of spondyloarthritis in the People’s Republic of China: review of the literature and commentary. Semin Arthritis Rheum 37:39–47

    Article  PubMed  Google Scholar 

  3. Dean LE, Jones GT, MacDonald AG et al (2014) Global prevalence of ankylosing spondylitis. Rheumatology 53:650–657 (Oxford)

    Article  PubMed  Google Scholar 

  4. Brown MA, Laval SH, Brophy S et al (2000) Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 59:883–886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Brewerton DA, Hart FD, Nicholls A et al (1973) Ankylosing spondylitis and HL-A 27. Lancet 1:904–907

    Article  PubMed  CAS  Google Scholar 

  6. Brown MA, Kennedy LG, Darke C et al (1998) The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis. Arthritis Rheum 41:460–465

    Article  PubMed  CAS  Google Scholar 

  7. Duan Z, Pan F, Zeng Z et al (2012) Interleukin-23 receptor genetic polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis. Rheumatol Int 32:1209–1214

    Article  PubMed  CAS  Google Scholar 

  8. Prokunina L, Castillejo-Lopez C, Oberg F et al (2002) A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 32:666–669

    Article  PubMed  CAS  Google Scholar 

  9. Nishimura H, Okazaki T, Tanaka Y et al (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322

    Article  PubMed  CAS  Google Scholar 

  10. Nishimura H, Honjo T (2001) PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol 22:265–268

    Article  PubMed  CAS  Google Scholar 

  11. Latchman Y, Wood CR, Chernova T et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

    Article  PubMed  CAS  Google Scholar 

  12. Freeman GJ, Long AJ, Iwai Y et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Ansari MJ, Salama AD, Chitnis T et al (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198:63–69

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Salama AD, Chitnis T, Imitola J et al (2003) Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 198:71–78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Greenwald RJ, Oosterwegel MA, van der Woude D et al (2002) CTLA-4 regulates cell cycle progression during a primary immune response. Eur J Immunol 32:366–373

    Article  PubMed  CAS  Google Scholar 

  16. 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 

  17. Liu X, Hu LH, Li YR et al (2011) Programmed cell death 1 gene polymorphisms is associated with ankylosing spondylitis in Chinese Han population. Rheumatol Int 31:209–213

    Article  PubMed  Google Scholar 

  18. Qian BP, Wang XQ, Qiu Y et al (2013) An exon polymorphism of programmed cell death 1 gene is associated with both the susceptibility and thoracolumbar kyphosis severity of ankylosing spondylitis in a Chinese Han population. J Orthop Sci 18:514–518

    Article  PubMed  CAS  Google Scholar 

  19. Soleimanifar N, Amirzargar AA, Mahmoudi M et al (2011) Study of programmed cell death 1 (PDCD1) gene polymorphims in Iranian patients with ankylosing spondylitis. Inflammation 34:707–712

    Article  PubMed  Google Scholar 

  20. Lee SH, Lee YA, Woo DH et al (2006) Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population. Arthritis Res Ther 8:R163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Yang Q, Liu Y, Liu D et al (2011) Association of polymorphisms in the programmed cell death 1 (PD-1) and PD-1 ligand genes with ankylosing spondylitis in a Chinese population. Clin Exp Rheumatol 29:13–18

    PubMed  Google Scholar 

  22. Huang CH, Wei JC, Chen CC et al (2014) Associations of the PTPN22 and CTLA-4 genetic polymorphisms with Taiwanese ankylosing spondylitis. Rheumatol Int 34:683–691

    Article  PubMed  CAS  Google Scholar 

  23. Azizi E, Massoud A, Amirzargar AA et al (2010) Association of CTLA4 gene polymorphism in Iranian patients with ankylosing spondylitis. J Clin Immunol 30:268–271

    Article  PubMed  CAS  Google Scholar 

  24. Lee WY, Chang YH, Lo MK et al (2010) Polymorphisms of cytotoxic T lymphocyte-associated antigen-4 and cytokine genes in Taiwanese patients with ankylosing spondylitis. Tissue Antigens 75:119–126

    Article  PubMed  CAS  Google Scholar 

  25. Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  PubMed Central  Google Scholar 

  26. Brittain EH, Fay MP, Follmann DA (2012) A valid formulation of the analysis of noninferiority trials under random effects meta-analysis. Biostatistics 13:637–649

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chootrakool H, Shi JQ, Yue R (2011) Meta-analysis and sensitivity analysis for multi-arm trials with selection bias. Stat Med 30:1183–1198

    PubMed  Google Scholar 

  28. Sterne JA, Egger M, Smith GD (2001) Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ 323:101–105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Munafo MR, Clark TG, Flint J (2004) Assessing publication bias in genetic association studies: evidence from a recent meta-analysis. Psychiatry Res 129:39–44

    Article  PubMed  Google Scholar 

  30. Chen X, Zhou X, Li X et al (2014) Effects of Tumor Necrosis Factor Inhibitor on Serum Level of HLA-B27 and PDCD-1 in Patients with Ankylosing Spondylitis. Cell Biochem Biophys 70:1453–1457

    Article  PubMed  CAS  Google Scholar 

  31. Bautista-Caro MB, Arroyo-Villa I, Castillo-Gallego C et al (2014) Decreased frequencies of circulating Follicular Helper T Cell counterparts and plasmablasts in Ankylosing Spondylitis patients naive for TNF blockers. PLoS One 9:e107086

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Xiao F, Zhang HY, Liu YJ et al (2013) Higher frequency of peripheral blood interleukin 21 positive follicular helper T cells in patients with ankylosing spondylitis. J Rheumatol 40:2029–2037

    Article  PubMed  CAS  Google Scholar 

  33. Chen MH, Chen WS, Lee HT et al (2011) Inverse correlation of programmed death 1 (PD-1) expression in T cells to the spinal radiologic changes in Taiwanese patients with ankylosing spondylitis. Clin Rheumatol 30:1181–1187

    Article  PubMed  Google Scholar 

  34. Bleil J, Maier R, Hempfing A et al (2014) Histomorphologic and histomorphometric characteristics of zygapophyseal joint remodeling in ankylosing spondylitis. Arthritis Rheumatol 66:1745–1754

    Article  PubMed  Google Scholar 

  35. Huang ZX, Tan JH, Li TW et al (2013) Influence of sinomenine on protein profiles of peripheral blood mononuclear cells from ankylosing spondylitis patients: a pharmacoproteomics study. Chin Med J 126:3645–3650 (Engl)

    PubMed  CAS  Google Scholar 

  36. Britanova OV, Staroverov DB, Chkalina AV et al (2011) Single high-dose treatment with glucosaminyl-muramyl dipeptide is ineffective in treating ankylosing spondylitis. Rheumatol Int 31:1101–1103

    Article  PubMed  CAS  Google Scholar 

  37. Yang ZX, Liang Y, Zhu Y et al (2007) Increased expression of Toll-like receptor 4 in peripheral blood leucocytes and serum levels of some cytokines in patients with ankylosing spondylitis. Clin Exp Immunol 149:48–55

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Duftner C, Goldberger C, Falkenbach A et al (2003) Prevalence, clinical relevance and characterization of circulating cytotoxic CD4+ CD28-T cells in ankylosing spondylitis. Arthritis Res Ther 5:R292–R300

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. van der Paardt M, Crusius JB, de Koning MH et al (2003) CARD15 gene mutations are not associated with ankylosing spondylitis. Genes Immun 4:77–78

    Article  PubMed  CAS  Google Scholar 

  40. Hickey EJ, Raje RR, Reid VE et al (2001) Diclofenac induced in vivo nephrotoxicity may involve oxidative stress-mediated massive genomic DNA fragmentation and apoptotic cell death. Free Radic Biol Med 31:139–152

    Article  PubMed  CAS  Google Scholar 

  41. Huang CH, Wong RH, Wei JC et al (2011) Effects of genetic polymorphisms of programmed cell death 1 and its ligands on the development of ankylosing spondylitis. Rheumatology 50:1809–1813 (Oxford)

    Article  PubMed  CAS  Google Scholar 

  42. Lee YH, Bae SC, Kim JH et al (2014) Meta-analysis of genetic polymorphisms in programmed cell death 1: Associations with rheumatoid arthritis, ankylosing spondylitis, and type 1 diabetes susceptibility. Z Rheumatol 74(3):230–239

    Article  CAS  Google Scholar 

  43. Yang M, Zou Y, Bai Y et al (2014) The programmed cell death 1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T and PD 1.9 C/T) and susceptibility to ankylosing spondylitis: a meta-analysis. J Orthop Sci 20(1):55–63

    Article  PubMed  CAS  Google Scholar 

  44. Reveille JD, Sims AM, Danoy P et al (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123–127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgments

We thank all our colleagues working in the Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology.

Funding

This work was supported by funding from the Research Special Fund for Public Welfare Industry of Health (201202004), and the National Natural Science Foundation of China Grants (81172857, 81373188), the Chinese National High Technology Research and Development Program, Ministry of Science and Technology Grants (2011AA02A113), and the National Science Technology Pillar Program in the 12th 5-year Plan (2014BAI07B00).

Author information

Author notes

    Authors and Affiliations

    1. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 41 Damucang Hutong, Xicheng District, Beijing, 100032, China

      Si Chen, Yuan Li, Chuiwen Deng, Jing Li, Xiaoting Wen, Ziyan Wu, Chaojun Hu, Shulan Zhang, Ping Li, Xuan Zhang, Fengchun Zhang & Yongzhe Li

    Authors
    1. Si Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yuan Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Chuiwen Deng
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Jing Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Xiaoting Wen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ziyan Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Chaojun Hu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Shulan Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Ping Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Xuan Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Fengchun Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Yongzhe Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Yongzhe Li.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Ethical standard

    The study was approved by the Ethics Committee of the Peking Union Medical College Hospital.

    Additional information

    Si Chen, Yuan Li and Chuiwen Deng have contributed equally to this manuscript.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chen, S., Li, Y., Deng, C. et al. The associations between PD-1, CTLA-4 gene polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis and systemic review. Rheumatol Int 36, 33–44 (2016). https://doi.org/10.1007/s00296-015-3327-9

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00296-015-3327-9

    Keywords

    Search

    Navigation