Skip to main content
SpringerLink
Log in

Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta-analysis based on 1366 subjects

  • Meta-analysis
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

Perforin (PRF1) gene mutation can cause the onset of hemophagocytic lymphohistiocytosis (HLH). It has reported that PRF1 Ala91Val polymorphism was related with HLH risk. In the meta-analysis, we aim to evaluate the association between PRF1 Ala91Val polymorphism and HLH risk.

Methods

We accomplished a meta-analysis of six published case–control studies including 391 patients with HLH and 975 controls. We evaluated the quality of each study through Newcastle–Ottawa Scale (NOS). Data analysis was performed with Stata software.

Results

In general, all studies were of high quality (NOS score higher than 7). There were statistically significant between the PRF1 Ala91Val polymorphism and HLH risk though the pooled analysis [for Ala/Val vs. Ala/Ala: pooled odds ratio (OR) = 3.22, 95% confidence interval (CI) 1.08–9.56, P = 0.035, random model; for Ala/Val + Val/Val vs. Ala/Ala: pooled OR = 2.96, 95% CI 1.14–7.69, P = 0.025, random model]. Furthermore, sensitivity analysis also revealed a relationship between PRF1 Ala91Val polymorphism and HLH risk (for Ala/Val vs. Ala/Ala: pooled OR = 5.236, 95% CI 2.72–10.08, P < 0.000, I2 = 12.1%, Pheterogeneity = 0.332; for Ala/Val + Val/Val vs. Ala/Ala, pooled OR = 4.856, 95% CI 2.66–8.85, P < 0.000, I2 = 5.9%, Pheterogeneity = 0.373). Funnel plot and Egger’s test did not indicate obvious published bias (P = 0.841 for Ala/Val vs. Ala/Ala; P = 0.284 for Ala/Val + Val/Val vs. Ala/Ala).

Conclusion

This meta-analysis indicated that PRF1 Ala91Val polymorphism affects the factor for developing HLH and future studies of PRF1 Ala91Val on the onset of HLH will be guaranteed.

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.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 2018;13:27–49.

    CAS  Google Scholar 

  2. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.

    Google Scholar 

  3. Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis: advances in pathophysiology, diagnosis, and treatment. J Pediatr. 2013;163:1253–9.

    Google Scholar 

  4. Zhang L, Li Z, Liu W, Ma H, Wang T, Zhang R. Genetic characterization of pediatric primary hemophagocytic lymphohistiocytosis in China: a single-center study. Ann Hematol. 2019;98:2303–10.

    CAS  Google Scholar 

  5. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118:5794–8.

    CAS  PubMed Central  Google Scholar 

  6. Edwards KM, Davis JE, Browne KA, Sutton VR, Trapani JA. Anti-viral strategies of cytotoxic T lymphocytes are manifested through a variety of granule-bound pathways of apoptosis induction. Immunol Cell Biol. 1999;77:76–89.

    CAS  Google Scholar 

  7. Lichtenheld MG, Olsen KJ, Lu P, Lowrey DM, Hameed A, Hengartner H, et al. Structure and function of human perforin. Nature. 1988;335:448–51.

    CAS  Google Scholar 

  8. Lowin B, Peitsch MC, Tschopp J. Perforin and granzymes: crucial effector molecules in cytolytic T lymphocyte and natural killer cell-mediated cytotoxicity. Curr Top Microbiol Immunol. 1995;198:1–24.

    CAS  Google Scholar 

  9. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233–46.

    CAS  Google Scholar 

  10. Zur Stadt U, Beutel K, Weber B, Kabisch H, Schneppenheim R, Janka G. A91V is a polymorphism in the Perforin gene not causative of FHLH phenotype. Blood. 2004;104:1909 (author reply 1910).

    CAS  Google Scholar 

  11. Molleran Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, et al. Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet. 2004;41:137–44.

    CAS  Google Scholar 

  12. Okur H, Ünal Ş, Balta G, Efendioğlu D, Çimen E, Çetin M, et al. The frequency of A91V in the perforin gene and the effect of tumor necrosis factor-α promoter polymorphism on acquired hemophagocytic lymphohistiocytosis. Turk J Haematol. 2011;28:125–30.

    CAS  Google Scholar 

  13. Trambas C, Gallo F, Pende D, Marcenaro S, Moretta L, De Fusco C, et al. A single amino acid change, A91V, leads to conformational changes that can impair processing to the active form of perforin. Blood. 2005;106:932–7.

    CAS  Google Scholar 

  14. Risma KA, Frayer RW, Filipovich AH, Sumegi J. Aberrant maturation of mutant Perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. J Clin Invest. 2006;116:182–92.

    CAS  Google Scholar 

  15. Voskoboinik I, Dunstone MA, Baran K, Whisstock JC, Trapani JA. Perforin: structure, function, and role in human immunopathology. Immunol Rev. 2010;235:35–54.

    CAS  Google Scholar 

  16. Kägi D, Hengartner H. Different roles for cytotoxic T cells in the control of infections with cytopathic versus noncytopathic viruses. Curr Opin Immunol. 1996;8:472–7.

    Google Scholar 

  17. Jaworowska A, Pastorczak A, Trelinska J, Wypyszczak K, Borowiec M, Fendler W, et al. Perforin gene variation influences survival in childhood acute lymphoblastic leukemia. Leuk Res. 2018;65:29–33.

    CAS  Google Scholar 

  18. Manso R, Rodríguez-Pinilla SM, Lombardia L, Ruiz de Garibay G, Del Mar LM, Requena L, et al. An A91V SNP in the perforin gene is frequently found in NK/T-cell lymphomas. PLoS One. 2014;9:e91521.

    PubMed Central  Google Scholar 

  19. Orilieri E, Cappellano G, Clementi R, Cometa A, Ferretti M, Cerutti E, et al. Variations of the perforin gene in patients with type 1 diabetes. Diabetes. 2008;57:1078–83.

    CAS  PubMed Central  Google Scholar 

  20. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.

    Google Scholar 

  21. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa (ON): Ottawa Hospital Research Institute; 2009. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 1 Jan 2012.

  22. Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15:388–400.

    CAS  Google Scholar 

  23. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    PubMed Central  Google Scholar 

  24. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    CAS  PubMed Central  Google Scholar 

  25. Donn R, Ellison S, Lamb R, Day T, Baildam E, Ramanan AV. Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic-onset juvenile idiopathic arthritis. Arthritis Rheumatol. 2008;58:869–74.

    CAS  Google Scholar 

  26. Zhang K, Johnson JA, Biroschak J, Villanueva J, Lee SM, Bleesing JJ, et al. Familial haemophagocytic lymphohistiocytosis in patients who are heterozygous for the A91V perforin variation is often associated with other genetic defects. Int J Immunogenet. 2007;34:231–3.

    CAS  Google Scholar 

  27. Busiello R, Fimiani G, Miano MG, Aricò M, Santoro A, Ursini MV, et al. A91V perforin variation in healthy subjects and FHLH patients. Int J Immunogenet. 2006;33:123–5.

    CAS  Google Scholar 

  28. Feldmann J, Le Deist F, Ouachée-Chardin M, Certain S, Alexander S, Quartier P, et al. Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis. Br J Haematol. 2002;117:965–72.

    CAS  Google Scholar 

  29. Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100:2266–7.

    CAS  Google Scholar 

  30. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286:1957–9.

    CAS  Google Scholar 

  31. Muralitharan S, Wali Y, Pathare AV. Perforin A91V polymorphism and putative susceptibility to hematological malignancies. Leukemia. 2006;20:2178.

    CAS  Google Scholar 

  32. Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, et al. Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia. 2006;20:1539–41.

    CAS  PubMed Central  Google Scholar 

  33. Santoro A, Cannella S, Trizzino A, Lo Nigro L, Corsello G, Aricò M. A single amino acid change A91V in perforin: a novel, frequent predisposing factor to childhood acute lymphoblastic leukemia? Haematologica. 2005;90:697–8.

    Google Scholar 

  34. Voskoboinik I, Sutton VR, Ciccone A, House CM, Chia J, Darcy PK, et al. Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood. 2007;110:1184–90.

    CAS  Google Scholar 

  35. An O, Gursoy A, Gurgey A, Keskin O. Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients. Protein Sci. 2013;22:823–39.

    CAS  PubMed Central  Google Scholar 

  36. Voskoboinik I, Thia MC, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood. 2005;105:4700–6.

    CAS  Google Scholar 

Download references

Acknowledgements

We thank Prof. Xian-Tao Zeng (Wuhan University) and Prof. Ling Zhang (Capital Medical University) who helped with this study.

Funding

This study was funded by National Science and Technology Key Projects (No. 2017ZX09304029001), the Beijing Municipal Science & Technology Commission (No. Z171100001017050), the National Natural Science Foundation of China (No. 81700186, 81800189), the Scientific Research Common Program of Beijing Municipal Commission of Education (No. KM201710025019), the Talent Training Project-Fostering Fund of National Natural Science Foundation of Beijing Children’s Hospital, Capital Medical University (No. GPY201713), the Special Fund of The Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority (No. XTZD20180202), the Guangdong Province Key Laboratory of Popular High Performance Computers of Shenzhen University (SZU-GDPHPCL2017).

Author information

Author notes

    Authors and Affiliations

    1. Beijing Children’s Hospital, Nanlishi Road No. 56, Xicheng District, Beijing, China

      Guang-Hua Zhu, Li-Ping Zhang, Zhi-Gang Li, Ang Wei, Ying Yang, Yu Tian, Hong-Hao Ma, Dong Wang, Xiao-Xi Zhao, Yun-Ze Zhao, Na Li, Wei Liu, Tian-You Wang & Rui Zhang

    Authors
    1. Guang-Hua Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Li-Ping Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Zhi-Gang Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ang Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ying Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Yu Tian
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Hong-Hao Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Dong Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Xiao-Xi Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Yun-Ze Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Na Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Wei Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Tian-You Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Rui Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Contributions

    GHZ and LPZ designed and performed the literature search and drafted the manuscript. GHZ and LPZ contributed equally to this work. AW, YY, YT, HHM, DW, XXZ, YZZ, NL, ZGL, WL and TYW analyzed the data, and verified and discussed the studies. RZ amended the paper, designed the research, proofread the manuscript, supervised and approved the study.

    Corresponding author

    Correspondence to Rui Zhang.

    Ethics declarations

    Ethical approval

    This meta-analysis is not related to raw data of clinical patients. No need to go through Ethics Committee.

    Conflict of interest

    All authors declare that they have no conflict of interest.

    Additional information

    Publisher's Note

    Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary file 1 (DOC 62 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhu, GH., Zhang, LP., Li, ZG. et al. Associations between PRF1 Ala91Val polymorphism and risk of hemophagocytic lymphohistiocytosis: a meta-analysis based on 1366 subjects. World J Pediatr 16, 598–606 (2020). https://doi.org/10.1007/s12519-020-00351-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12519-020-00351-7

    Keywords

    Search

    Navigation