The genetic and functional significance of non-HLA polymorphisms in haematopoietic stem cell transplantation

Abstract

Haematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for many patients with malignant and non-malignant haematological diseases. However, its success is greatly reduced by the development of complications, including graft-versus-host disease (GVHD), infection and relapse. Human leukocyte antigen (HLA)-matching of patients and donors is essential in HSCT, but does not completely prevent such complications. Thus, it is extremely likely that non-HLA genes also have an impact. Naturally occurring polymorphisms within non-HLA genes have been suggested to contribute to some of the genetic disparity that exists between transplant patients and donors, consequently, they may have the potential to influence HSCT outcome. As a result, this study investigated the significance of non-HLA polymorphisms in HSCT. Polymorphisms in the genes of interleukin (IL) 2 (IL2, -330 T/G), 4 (IL4, -590 C/T), 6 (IL6, -174 G/C) and 10 (IL10, -592 A/C, -1082 G/A), IL-1 receptor antagonist (IL-1Ra (IL1RN), intron 2 VNTR), tumour necrosis factor α (TNFα (TNFA), intron 3 (GA)n), TNF receptor II (TNFRII (TNFRSF1B), -196 M/R), interferon γ (IFNγ (IFNG), intron 1 (CA)n), vitamin D receptor (VDR, intron 8 A/C, exon 9 T/C) and oestrogen receptor (ESR1, intron 1 A/G, intron 1 C/T) have been studied extensively in HLA-matched sibling transplantation, however, relatively little is known about their role in unrelated donor HSCT. This study therefore examined these polymorphisms in the unrelated donor setting. VDR intron 8 A/C, IFNG intron 1 (CA)n and IL6 -174 G/C were found to associate with GVHD in our cohort. The VDR intron 8 A,A and IFNG intron 1 3,3 genotypes correlated with severe acute GVHD (grades III-IV), whilst the IL6 -174 G,G genotype correlated with chronic GVHD. No genetic associations were demonstrated with any other clinical outcome. This study also examined the +2044 G/A polymorphism in the gene encoding IL-13 (IL13), an immunoregulatory cytokine that has been implicated in GVHD. This polymorphism has been widely studied for disease associations; however, its role in HLA-matched sibling and unrelated donor HSCT is currently unknown. In our transplant cohort the IL13 +2044 A allele was found to correlate significantly with both acute and chronic GVHD. Higher IL-13 expression was also observed in patients with these conditions, although this altered expression could not be directly attributed to IL13 +2044 G/A. The prognostic significance of pre-transplant IL-13 serum levels was also investigated. No associations were observed between IL-13 expression and GVHD. Elevated pre-transplant IL-13 serum levels did, however, correlate with post-transplant relapse and Hodgkin disease in two independent cohorts. Again, this altered expression could not be directly attributed to the IL13 +2044 G/A polymorphism. This study clearly demonstrates that non-HLA polymorphisms influence the outcome of both HLA-matched sibling and unrelated donor HSCT. Thus, in the future, genotyping with respect to a panel of non-HLA polymorphisms may be used to complement HLA typing, increase the ability to predict the risk of transplant complications and allow post-transplant treatment strategies to be tailored to an individual.