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The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation

Lookup NU author(s): Jean Norden, Dr Kim Pearce, Professor Julie Irving, Professor Matthew Collin, Professor Anne Dickinson

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley-Blackwell, 2018.

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Abstract

Haematopoietic stem cell transplantation (HSCT) remains the only cure for most haematological malignancies, however, the mortality rate remains high. Complications after HSCT include relapse, graft versus host disease (GvHD), graft rejection and infection. Over the last few years several groups, have demonstrated that non-HLA gene polymorphisms can be predictive of outcome after HSCT. Since the glucocorticoid cortisol is pivotal in the regulation of the immune system, we decided to examine single nucleotide polymorphisms (SNPs) (rs6198, rs33388 and rs33389) within the glucocorticoid receptor (GR) and correlate with HSCT outcome. The training set consisted of patients (n=458) who underwent HSCT for acute leukaemia between 1983 and 2005. In the recipients, the absence of the ACT haplotype and absence of the T allele of rs33388 were associated with decreased OS and the absence of the ACT haplotype, the absence of the T allele of rs33388 and the presence of the ATA haplotype were associated with increased risk of relapse. In addition, the presence of the ACT haplotype in the recipient showed a trend to be associated with increased risk of cGvHD. The patients in this cohort received mainly myeloablative conditioning (n=327). The SNPs in the glucocorticoid receptor were then investigated in a validation set (n=251) of HSCT patients transplanted for acute leukaemia from 2006. This cohort contained significantly more patients that had received reduced intensity conditioning (RIC). Some of the results could be validated in these patients. However, contrary to the training set, the absence of the haplotype ACT in the donor in this cohort was associated with increased risk of cGvHD. Differences in the conditioning were shown to influence the results. These results are the first to associate GR SNPs with HSCT outcome and demonstrate the inherent problems of replicating SNP association studies in HSCT, due to different pre-transplant regimens.


Publication metadata

Author(s): Norden J, Pearce K, Irving J, Collin M, Wang X, Wolff D, Kolb HJ, Socie G, Kuzmina Z, Greinix H, Holler E, Rocha V, Gluckman E, Hromadnikova I, Dickinson AM

Publication type: Article

Publication status: Published

Journal: International Journal of Immunogenetics

Year: 2018

Volume: 45

Issue: 5

Pages: 247-256

Print publication date: 01/10/2018

Online publication date: 25/07/2018

Acceptance date: 31/05/2018

ISSN (print): 1744-3121

ISSN (electronic): 1744-313X

Publisher: Wiley-Blackwell

URL: https://doi.org/10.1111/iji.12380

DOI: 10.1111/iji.12380


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