Pharmacogenetics of steroid-responsive acute graft-versus-host disease

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Abstract

Glucocorticoids are central to effective therapy of acute graft-versus-host disease (GVHD). However, only about half of the patients respond to steroids in initial therapy. Based on postulated mechanisms for anti-inflammatory effectiveness, we explored genetic variations in glucocorticoid receptor, co-chaperone proteins, membrane transporters, inflammatory mediators, and variants in the T-cell receptor complex in hematopoietic cell transplant recipients with acute GVHD requiring treatment with steroids and their donors toward response at day 28 after initiation of therapy. A total of 300 recipient and donor samples were analyzed. Twenty-three SNPs in 17 genes affecting glucocorticoid pathways were included in the analysis. In multiple regression analysis, donor SNP rs3192177 in the ZAP70 gene (O.R. 2.8, 95% CI: 1.3-6.0, P=.008) and donor SNP rs34471628 in the DUSPI gene (O.R. 0.3, 95% CI: 0.1-1.0, P=.048) were significantly associated with complete or partial response. However, after adjustment for multiple testing, these SNPs did not remain statistically significant. Our results, on this small, exploratory, hypothesis generating analysis suggest that common genetic variation in glucocorticoid pathways may help identify subjects with differential response to glucocorticoids. This needs further assessment in larger datasets and if validated could help identify subjects for alternative treatments and design targeted treatments to overcome steroid resistance.

Original languageEnglish (US)
Article numbere12949
JournalClinical Transplantation
Volume31
Issue number5
DOIs
StatePublished - May 2017

Bibliographical note

Funding Information:
Support for this study was provided by grant #U10HL069294 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute, along with contributions by Eisai Inc., Hospira Inc., Roche Laboratories Inc., and Immunex Corporation, a wholly owned subsidiary of Amgen Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the above mentioned parties. Additional support was provided to the Blood and Marrow Transplant Clinical Trials Network by the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases for the ancillary studies, Analysis of Serum Biomarkers Related to aGVHD Treatment Responsiveness and “Pharmacogenetics of Steroid Responsiveness in aGVHD”. This manuscript was prepared using BMT CTN 0302 Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the BMT CTN 0302 or the NHLBI. We also acknowledge all centers who enrolled in the BMT CTN 0302 trial.

Publisher Copyright:
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords

  • SNPs
  • allogeneic
  • graft-versus-host disease
  • hematopoietic cell transplant
  • pharmacogenetics

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