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Allografting

Association of IL6 and CCL2 gene polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation

Abstract

Various polymorphisms of non-HLA genes have recently been investigated as candidate risk factors in allogeneic haematopoietic SCT (aHSCT). Our study aimed at exploring possible associations of IL6 and CCL2 single nucleotide polymorphisms (SNP) with aHSCT outcome. A total of 166 HLA-identical aHSCT pairs recruited in were genotyped for IL6 −174 G/C, IL6 −597 G/A, CCL2 −2518 A/G and CCL2 −2076 A/T SNPs by PCR with sequence-specific primers (PCR-SSP). The association between IL6 −174 GG genotype and increased risk of acute GVHD was found in whole study group (P=0.03) and in the subgroup of related aHSCT (P=0.01), association between IL6 −597 GG genotype and the occurrence of acute GVHD was detected only in the related aHSCT pairs (P=0.02). Furthermore, reduction in OS was revealed among recipients possessing IL6 −174*G allele in the group of related aHSCT pairs (P=0.04). Presence of CCL2 −2076 TT genotype was associated with decrease of OS (P=0.04) and increase of TRM (P=0.02) in patients transplanted by related donor. These results, in the context of previous findings, suggest that IL6 gene polymorphisms may be associated with aHSCT outcome, particularly in patients transplanted from a related donor.

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References

  1. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    Article  CAS  PubMed  Google Scholar 

  2. Dickinson AM, Middleton PG, Rocha V, Gluckman E, Holler E, Eurobank members. Genetic polymorphisms predicting the outcome of bone marrow transplants. Br J Haematol 2004; 127: 479–490.

    Article  CAS  PubMed  Google Scholar 

  3. Dickinson AM, Charron D . Non-HLA immunogenetics in hematopoietic stem cell transplantation. Curr Opin Immunol 2005; 17: 517–525.

    Article  CAS  PubMed  Google Scholar 

  4. Sociè G, Loiseau P, Tamouza R, Janin A, Busson M, Gluckman E et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation 2001; 72: 699–706.

    Article  PubMed  Google Scholar 

  5. Mullighan C, Heatley S, Doherty K, Szabo F, Grigg A, Hughes T et al. Non-HLA immunogenetic polymorphisms and the risk of complications after allogeneic hemopoietic stem-cell transplantation. Transplantation 2004; 27: 587–596.

    Article  Google Scholar 

  6. Bertinetto FE, Dall’Omo AM, Mazzola GA, Rendine S, Berrino M, Bertola L et al. Role of non-HLA genetic polymorphisms in graft-versus-host disease after haematopoietic stem cell transplantation. Int J Immunogenet 2006; 33: 375–384.

    Article  CAS  PubMed  Google Scholar 

  7. Fishman D, Faulds G, Jeffrey R, Mohamed-Ali V, Yudkin JS, Humphries S et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenil chronic arthritis. J Clin Invest 1998; 102: 1369–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cavet J, Dickinson AM, Norden J, Taylor PR, Jackson GH, Middleton PG . Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 2001; 98: 1594–1600.

    Article  CAS  PubMed  Google Scholar 

  9. Karabon L, Wysoczanska B, Bogunia-Kubik K, Suchnicki K, Lange A . IL-6 and IL-10 promoter gene polymorphisms of patients and donors of allogeneic sibling hematopoietic stem sell transplants associate with the risk of acute graft-versus-host disease. Hum Immunol 2005; 66: 700–710.

    Article  CAS  PubMed  Google Scholar 

  10. Zlotnik A, Yoshie O, Nomiyama H . The chemokine and chemokine receptor superfamilies and their molecular evaluation. Genome Biol 2006; 7: 243.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wysocki CA, Panoskaltsis-Mortari A, Blazar BR, Serody JS . Leukocyte migration and graft-versus-host disease. Blood 2005; 105: 4191–4199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rovin BH, Lu L, Saxena R . A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression. Biochem Biophys Res Commun 1999; 259: 344–348.

    Article  CAS  PubMed  Google Scholar 

  13. Lacha J, Hribova P, Kotsch K, Brabcova I, Bartosova K, Volk HD et al. Effect of cytokines and chemokines (TGF-beta, TNF-alpha, IL-6, IL-10, MCP-1, RANTES) gene polymorphisms in kidney recipients on posttransplantation outcome: influence of donor-recipient match. Transplant Proc 2005; 37: 764–766.

    Article  CAS  PubMed  Google Scholar 

  14. Schröppel B, Fischereder M, Lin M, Marder B, Schiano T, Krämer BK et al. Analysis of gene polymorphisms in the regulatory region of MCP-1, RANTES and CCR5 in liver transplant recipients. J Clin Immunol 2002; 22: 381–385.

    Article  PubMed  Google Scholar 

  15. Kubistova Z, Mrazek F, Tudos Z, Kriegova E, Ambruzova Z, Mytilineos J et al. Distribution of 22 cytokine gene polymorphisms in the healthy Czech population. Int J Immunogenet 2006; 33: 261–267.

    Article  CAS  PubMed  Google Scholar 

  16. Bunce M, O’Neill CM, Barnardo MC, Krausa P, Browning MJ, Morris PJ et al. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens 1995; 46: 355–367.

    Article  CAS  PubMed  Google Scholar 

  17. Excoffier L, Laval G, Schneider S . Arlequin ver. 3.0: an integrated software package for population genetics data analysis. Evol Bioinform Online 2005; 1: 47–50.

    Article  CAS  Google Scholar 

  18. Dickinson AM, Middleton PG . Beyond the HLA typing age: genetic polymorphisms predicting transplant outcome. Blood Rev 2005; 19: 333–340.

    Article  CAS  PubMed  Google Scholar 

  19. Dickinson AM . Risk assessment in haematopoietic stem cell transplantation: pre-transplant patient and donor factors: non-HLA genetics. Best Pract Res Clin Haematol 2007; 20: 189–207.

    Article  CAS  PubMed  Google Scholar 

  20. Rocha V, Franco RF, Porcher R, Bittencourt H, Silva Jr WA, Latouche A et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood 2002; 100: 3908–3918.

    Article  CAS  PubMed  Google Scholar 

  21. Jaksch M, Mattsson J . The pathophysiology of acute graft-versus-host disease. Scand J Immunol 2005; 61: 398–409.

    Article  CAS  PubMed  Google Scholar 

  22. Holler E . Cytokines, viruses, and graft-versus-host disease. Curr Opin Hematol 2002; 9: 479–484.

    Article  PubMed  Google Scholar 

  23. Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, van der Helm-van Mil AH et al. Epidemiological Investigation of Rheumatoid Arthritis study group. gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 2007; 80: 867–875.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Huttunen R, Aittoniemi J, Laine J, Vuento R, Karjalainen J, Rovio AT et al. Gene-environment interaction between MBL2 genotype and smoking, and the risk of gram-positive bacteraemia. Scand J Immunol 2008; 68: 438–444.

    Article  CAS  PubMed  Google Scholar 

  25. Holler E, Rogler G, Brenmoehl J, Hahn J, Herfarth H, Greinix H et al. Prognostic significance of NOD2/CARD15 variants in HLA-identical sibling hematopoietic stem cell transplantation: effect on long-term outcome is confirmed in 2 independent cohorts and may be modulated by the type of gastrointestinal decontamination. Blood 2006; 107: 4189–4193.

    Article  CAS  PubMed  Google Scholar 

  26. Díez-Campelo M, Pérez-Simón JA, Ocio EM, Castilla C, González-Porras JR, Sánchez-Guijo FM et al. CD34+ cell dose and outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation. Leuk Lymphoma 2005; 46: 177–183.

    Article  PubMed  Google Scholar 

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Acknowledgements

Technical assistance of S Zachova, M Lukesova, J Onderkova and A Stahelova is gratefully acknowledged. We thank I Kemperle for collection of clinical data of Slovenian aHSCT pairs. This study was supported by the Research Programme of the Ministry of Education, Youth and Sports No. 6198959205 and the Internal Grant Agency of the Ministry of Health No. NR9099.

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Correspondence to M Petrek.

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Supplementary Information accompanies the paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)

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Ambruzova, Z., Mrazek, F., Raida, L. et al. Association of IL6 and CCL2 gene polymorphisms with the outcome of allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 44, 227–235 (2009). https://doi.org/10.1038/bmt.2009.16

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