Elsevier

International Immunopharmacology

Volume 43, February 2017, Pages 62-69
International Immunopharmacology

Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant

https://doi.org/10.1016/j.intimp.2016.12.007Get rights and content

Highlights

  • Association of rs7574865 polymorphism in donors with outcomes after HSCT

  • Presence of TT genotype increases susceptibility to CMV infection.

  • Possible association of rs7574865 with a weaker immune response in recipients

Abstract

STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P = 0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P = 0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes.

Introduction

Signal transducer and activator of transcription 4 (STAT4) is a member of the JAK-STAT pathway which is a vital signaling pathway in the immune response. The STAT protein is phosphorylated by Janus kinase (JAK) receptors on the cell surface after cytokine activation and translocates into the nucleus to initiate transcription of target genes [1]. It is the only tissue-specific STAT, expressed in myeloid and lymphoid tissues and has most commonly been associated with the regulation of interleukin-12 (IL-12) and its biological functions [2]. IL-12 binds specifically to two receptor subunits expressed on natural killer (NK) cells and activated B and T cells [3]. It is responsible for the production of IFN-γ, monocyte activation and T-helper type 1 (TH1) cell differentiation [4]. Therefore it is a critical mediator of the immune response and it is highly plausible that any change in STAT4 activity or expression can alter the function and response of the immune system, leading to autoimmune disorders or immunosuppression.

As a matter of fact, many STAT4 polymorphisms have increasingly been associated with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) [5], rheumatoid arthritis (RA) [6] etc. in various populations [7], [8], [9], [10]. In particular, evidence has pointed to the presence of polymorphism rs7574865 G/T as having the strongest associations. The presence of the T allele showed significant increase in odds ratio for SLE, RA, type 1 diabetes (T1D), Systemic Sclerosis (SSc) and Primary Sjogren's Syndrome (pSS) [11] and possibly associated with Juvenile Idiopathic Arthritis (JIA) and Primary Antiphospholipid Syndrome (APS) [12], [13]. In addition, the TT genotype has been proven to increase susceptibility to autoimmune thyroid diseases (AITD) [14]. Its minor T allele has also been proven to be associated with acute renal allograft rejection [15], further implying a significant role in the immune response. Therefore we looked into the possibility of an association of the rs7574865 G/T polymorphism with other transplant outcomes as well, especially in hematopoietic stem cell transplant (HSCT).

Section snippets

Study population

The study population consisted of pediatric patients with acute leukemia who underwent hematopoietic stem cell transplantation between November 2001 and April 2014 in the Seoul National University Children's Hospital. Out of 279 patients who underwent HSCT in this period, only 201 showed chimerism with donor cells. Out of this 201, only 161 produced viable DNA samples from HLA-matched transplants, resulting in a final of 161 patient samples used in this study. Peripheral blood or bone marrow

Rs7574865 genotyping

161 patient samples were analyzed for the rs7574865 polymorphism genotype. 78 (48.4%) patients were found to have the homozygous GG genotype, 69 (42.9%) had the heterozyous GT phenotype while 14 (8.7%) had the homozygous TT genotype. This is in consensus with the population average of about 10% for the TT genotype [14], [19]. This along with other baseline and demographic clinical characteristics of patients involved in the study are listed in Table 1.

Cumulative incidence

The influence of the genotypes was compared

Discussion

HSCT is now the common practice in the treatment of congenital or acquired hematologic malignancies or immunological disorders [24]. However, the success of HSCT hinges on the careful balance of the donor immune response to elicit a Graft vs Tumor effect [25] while keeping the recipient's immune response carefully in check to prevent GvHD and rejection of the graft but minimise the risk of infections [26]. Hence research on changes that can occur in an individual's immune response stands to

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT and Future Planning (2016M3A9D3026905) and by a grant (16183MFDS541) from the Ministry of Food and Drug Safety in 2016.

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