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Genetic susceptibility to acute graft versus host disease in pediatric patients undergoing HSCT

Bone Marrow Transplantation volume 56, pages 2697–2704 (2021)Cite this article

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Abstract

The most frequent complication of allogeneic hematopoietic stem cell transplantation is acute Graft versus Host Disease (aGVHD). Proliferation and differentiation of donor T cells initiate inflammatory response affecting the skin, liver, and gastrointestinal tract. Besides recipient–donor HLA disparities, disease type, and the conditioning regimen, variability in the non-HLA genotype have an impact on aGVHD onset, and genetic variability of key cytokines and chemokines was associated with increased risk of aGVHD. To get further insight into the recipient genetic component of aGVHD grades 2–4 in pediatric patients, we performed an exome-wide association study in a discovery cohort (n = 87). Nine loci sustained correction for multiple testing and were analyzed in a validation group (n = 168). Significant associations were replicated for ERC1 rs1046473, PLEK rs3816281, NOP9 rs2332320 and SPRED1 rs11634702 variants through the interaction with non-genetic factors. The ERC1 variant was significant among patients that received the transplant from HLA-matched related individuals (p = 0.03), bone marrow stem cells recipients (p = 0.007), and serotherapy-negative patients (p = 0.004). NOP9, PLEK, and SPRED1 effects were modulated by stem cell source, and serotherapy (p < 0.05). Furthermore, ERC1 and PLEK SNPs correlated with aGVHD 3-4 independently of non-genetic covariates (p = 0.02 and p = 0.003). This study provides additional insight into the genetic component of moderate to severe aGVHD.

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Fig. 1: Cumulative incidence of aGVHD 2–4 in relation to top-ranking loci identified through validation analysis of replication cohort.
Fig. 2: Cumulative incidence of aGVHD 3–4 in replication cohort relative to the variants in ERC1 and PLEK genes.

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Data availability

The datasets used and/or analyzed during the current study are available upon request. The request should be made to the data access committee composed of senior authors of this study: Dr. M. Krajinovic, maja.krajinovic@umontreal.ca; Dr. H. Bittencourt, henrique.bittencourt.hsj@ssss.gouv.qc.ca; Dr. M. Ansari, marc.ansari@hcuge.ch, and President of Ethics committee at SJUHC, G. Cardinal, genevieve.cardinal@recherche-ste-justine.qc.ca.

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Acknowledgements

Reported On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation. The authors would like to thank all patients and their parents for the participation in the study, as well as all study collaborators for their valuable contribution.

Funding

This investigation was supported by grants from the Swiss National Science Foundation (Grant No. 153389), CANSEARCH Foundation, AOK Foundation, and Foundation of Charles-Bruneau.

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Authors and Affiliations

  1. Cansearch research platform for paediatric oncology and haematology, Department of Paediatrics, Gynaecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland

    Marc Ansari, Tiago Nava, Simona Jurkovic Mlakar & Chakradhara Rao S. Uppugunduri

  2. Department of Women, Child and Adolescent, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland

    Marc Ansari, Tiago Nava, Simona Jurkovic Mlakar & Chakradhara Rao S. Uppugunduri

  3. Charles-Bruneau Cancer Center, Sainte-Justine University Health Center (SJUHC), Montreal, QC, Canada

    Kateryna Petrykey, Mohamed Aziz Rezgui, Veronica Del Vecchio, Jacques Cortyl, Milad Ameur, Patrick Beaulieu, Pascal St-Onge, Yves Théoret, Daniel Sinnett, Henrique Bittencourt & Maja Krajinovic

  4. Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada

    Kateryna Petrykey, Veronica Del Vecchio, Milad Ameur, Yves Théoret & Maja Krajinovic

  5. Clinical Pharmacology Unit, Sainte-Justine University Health Center (SJUHC), Montreal, QC, Canada

    Yves Théoret & Maja Krajinovic

  6. Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands

    Imke H. Bartelink & Jaap-Jan Boelens

  7. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Pharmacology and Pharmacy, Cancer Center Amsterdam, Amsterdam, The Netherlands

    Imke H. Bartelink

  8. Stem cell transplantation and cellular therapy program, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jaap-Jan Boelens

  9. Department of Pediatrics, Division of Immunology, Infectious Diseases and SCT, Leiden University Medical Center, Leiden, The Netherlands

    Robbert G. M. Bredius

  10. Pediatric Hematology Department, Robert Debré Hospital, Assistance Publique, Hôpitaux de Paris and Paris-Diderot University, Paris, France

    Jean-Hugues Dalle

  11. Department of Oncology, Alberta Children’s Hospital, Calgary, AB, Canada

    Victor Lewis & Bill S. Kangarloo

  12. Department of Hematology, Oncology, and Stem Cell Transplantation University Children’s Hospital Regensburg, Regensburg, Germany

    Selim Corbacioglu

  13. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada

    Daniel Sinnett, Henrique Bittencourt & Maja Krajinovic

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  1. Marc Ansari
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Contributions

M.A., H.B., and M.K. designed the study; D.S. supervised WES analyses; P.S.-O. and P.B. contributed to bioinformatics analyses; Y.T., I.H.B., J.J.B., R.G.M.B., J.H.D., V.L., B.S.K., S.C., M.A., H.B., M.A.R. contributed to patients’ sample and data processing; K.P., J.C., V.D.V., and M.K. executed computational and statistical analysis; T.N., S.J.M., C.R.S.U. contributed to interpretation of results; M.A.R. and M.A. performed the replication analysis; M.K. drafted the manuscript and all authors revised it critically.

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Correspondence to Maja Krajinovic.

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The authors declare no competing interests.

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Written informed consent was obtained from every patient or parent/legal guardian. The study was conducted in accordance with the Declaration of Helsinki and was approved by Research Ethics Board of SJUHC.

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Ansari, M., Petrykey, K., Rezgui, M.A. et al. Genetic susceptibility to acute graft versus host disease in pediatric patients undergoing HSCT. Bone Marrow Transplant 56, 2697–2704 (2021). https://doi.org/10.1038/s41409-021-01386-8

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