|Year : 2022 | Volume
| Issue : 4 | Page : 255-262
Role of interleukin-6 polymorphism in acute graft-versus-host disease risk prediction in allogeneic hematopoietic stem cell transplantation
Afshan Noor1, Fahim Akhtar1, Saleem Ahmed Khan2, Mehreen Ali Khan3, Zaineb Akram3, Ghassan Umair Shamshad3, Humayoon Shafique Satti2, Qamar-Un-Nisa Chaudhry3, Fozia Fatima4
1 Department of Hematology, Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan
2 Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
3 Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Centre, National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan
4 Department of Rheumatology, Pak Emirates Military Hospital, National University of Medical Sciences, Rawalpindi, Pakistan
|Date of Submission||21-Oct-2021|
|Date of Decision||31-Jan-2022|
|Date of Acceptance||19-Apr-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Afshan Noor
Department of Hematology, Army Medical College, National University of Medical Sciences, Rawalpindi
Source of Support: None, Conflict of Interest: None
BACKGROUND: This study aimed to determine the association of single-nucleotide polymorphisms (SNPs) of interleukin-6 (IL-6) gene with the survival and disease status of patients after allogeneic hematopoietic stem cell transplantation.
MATERIALS AND METHODS: It was a prospective cohort study of total 102 participants, 51 patients along with their donors who had human leukocyte antigen-identical-matched allogeneic hematopoietic stem cell transplantation (aHSCT). Their pretransplant and posttransplant blood samples were collected for extraction of DNA for genotyping by sequence-specific primers polymerase chain reaction and gel electrophoresis followed by sequencing. The pre- and posttransplant levels of IL-6 were measured using enzyme-linked immunosorbent assay technique.
RESULTS: The mean age of our patients was 19.83 ± 12.5 years having males 65 (63.7%) and females 37 (36.3%). The frequency of −174G/C SNP among acute graft-versus-host disease (aGVHD) group was GG = 53.8%, GC = 34.6%, and CC = 11.5%, and for −597G/A SNP, it was GG = 69.2%, GA = 15.4%, and AA = 15.4%. Our results showed that the presence of G allele in both homozygous and heterozygous forms was associated with increased aGVHD incidence, while the homozygous CC and AA mutant genotypes correlated with the lowest number of cases of aGVHD. The polymorphism −597G/A was significantly associated with the incidence of aGVHD with P = 0.04. The GG genotype in −174G/C and −597G/A was found to be significantly associated with aGVHD with P < 0.0001. High serum levels of IL-6 pre- and posttransplant were found to be significantly associated with the incidence of aGVHD with P < 0.0001.
CONCLUSION: We concluded that the two SNPs − 174G/C and − 597G/A in the promoter region of IL-6 gene present either in donors or recipients predisposed to increase the risk of development of aGVHD following aHSCT. Their evaluation in our transplant setting may help in the risk stratification of transplant recipients early in time and predict the onset of aGVHD and mortality.
Keywords: Acute graft-versus-host disease, allogeneic hematopoietic stem cell transplantation, interleukin-6, polymerase chain reaction-sequence-specific primer, single-nucleotide polymorphism
|How to cite this article:|
Noor A, Akhtar F, Khan SA, Khan MA, Akram Z, Shamshad GU, Satti HS, Chaudhry QU, Fatima F. Role of interleukin-6 polymorphism in acute graft-versus-host disease risk prediction in allogeneic hematopoietic stem cell transplantation. J Appl Hematol 2022;13:255-62
|How to cite this URL:|
Noor A, Akhtar F, Khan SA, Khan MA, Akram Z, Shamshad GU, Satti HS, Chaudhry QU, Fatima F. Role of interleukin-6 polymorphism in acute graft-versus-host disease risk prediction in allogeneic hematopoietic stem cell transplantation. J Appl Hematol [serial online] 2022 [cited 2023 Sep 22];13:255-62. Available from: https://www.jahjournal.org/text.asp?2022/13/4/255/358703
| Introduction|| |
Allogeneic hematopoietic stem cell transplantation (aHSCT) has risen over the 50 years to become an important therapeutic technique for many hematological and nonhematological diseases., Its success is partly hindered by complications causing morbidity and mortality. Immunological incompatibility between donors and patients despite matching of the human leukocyte antigens (HLAs) is one of the major reasons. The major complications include graft-versus-host disease (GVHD) and often serious life-threatening infections and graft failure.
Acute GVHD (aGVHD) occurs in 30%–60% of patients of HSCT and usually occurs in the first 100 days, with skin, gastrointestinal tract, and liver being the principal target organs. The development of aGVHD is summarized in three phases: an afferent phase, efferent phase, and the effector phase. During the afferent phase, the exacerbation of inflammatory response is triggered by the release of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 (IL-1), and IL-6 resulting in the activation of antigen-presenting cells. This is followed by an efferent phase characterized by the active trafficking of T-cells and their expansion. Finally, the effector phase ensues via a cascade of inflammatory and cellular processes, resulting in further escalation of inflammation and tissue damage.
IL-6 is a pleiotropic cytokine. Its systemic levels are increased in patients with febrile illness, inflammatory diseases, hematological malignancies undergoing rigorous chemotherapy and allotransplantation as well as those who contracted COVID-19 infection., Certain single-nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene (particularly those at position −174G/C and −597G/A position) have shown to affect systemic levels of IL-6 in different clinical studies.,, This genetic control of IL-6 gene expression also has a role in predicting the incidence of aGVHD, treatment-related mortality (TRM), and transplant outcome. The presence of these SNPs either in patients or donors may result in increased secretion of IL-6 during the early posttransplant period, thereby contributing to the development of cytokine storm preceding aGVHD.,
This is the first study to report the prevalence of −174 G/C and −597 G/A polymorphisms in IL-6 gene among donor–recipient pairs in a matched-related aHSCT setting and its association with systemic levels of IL-6 and incidence of aGVHD in Pakistani patients.
| Materials and Methods|| |
Setting and study design
The study was carried out at Army Medical College, National University of Medical Sciences, in collaboration with the Stem Cell Research Laboratory, Armed Forces of Bone Marrow Transplant Centre, Pakistan, for 1-year duration, i.e., December 2019 to December 2020. Approval from the Ethics Committee of the institution was obtained before the study started via letter ERC/ID/82/2020, and the protocols conformed to the ethics guidelines of the 1975 Helsinki Declaration.
It was a prospective cohort study of 51 patients along with their donors for aHSCT. Inclusion criteria included patients aged <60 years undergoing HLA-matched related aHSCT for diseases including acute myeloid leukemia (13.7%), acute lymphoblastic leukemia (21.6%), aplastic anemia (21.6%), beta-thalassemia major (25.5%), and myelodysplastic syndrome (17.6%). All autologous stem cell transplants, aHSCT in patients aged >60 years, and those undergoing aHSCT from HLA-matched unrelated donors were excluded from the study. Other exclusions were failure to engraftment and/or early death within 2–3 weeks post aHSCT. Participants who signed the informed written consent for the use of biological samples and clinical information were included in the study while maintaining strict confidentiality of the data. A total of 46 participants, including patients and donors, were under the age of 18 years, and hence, written assent was obtained from their parents. The baseline demographic and clinical variables of the participants were collected on the predesigned data collection form [Table 1]. The disease risk was calculated using the European Society for Blood and Marrow Transplantation Risk Scoring System for hematological malignancies, Pesaro classification system for beta-thalassemia, Camitta criteria for aplastic anemia severity scoring and for myelodysplastic syndrome, and International Prognostic Scoring System-R. CMV status (IgM and IgG, respectively) of both patients and donors was determined through ELISA during the initial pretransplant workup. Post-HSCT CMV status was assessed from day +28 to day 100 on a weekly basis in the outpatient clinic.
|Table 1: Characteristics of the allogeneic hematopoietic stem cell transplantation|
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Blood sample collection
Peripheral blood samples of 4 ml were drawn from participants at two different time points, properly numbered, and stored at 4°C for DNA extraction and genetic studies. One-half volume of blood was centrifuged to separate serum in Eppendorf tubes, labeled, and stored at −80°C. The pretransplant sample was collected just before the start of induction chemotherapy, prior to aHSCT, while the follow-up blood sample was collected from patients on posttransplant 21st day. Posttransplant transfusions, if needed, were carried out through leukodepletion filters and gamma-irradiation. Minimum duration since the last transfusion was kept as 7 days from follow-up sample.
| Determination of interleukin-6|| |
The IL-6 levels were assessed by using an Invitrogen Thermo Fisher Human IL-6 ELISA Kit catalog number KAC 1261; Pub. No. MAN 0018799 was used using the manufacture's protocol.
Extraction of DNA and genotyping of interleukin-6 single-nucleotide polymorphisms
For DNA extraction, Qiagen DNA extraction kit (cat #158389) was used using the manufacture's protocol. DNA extracted was assessed on NanoDrop (Thermo Fisher Scientific) for quality and quantity.
For determining IL-6 −174G/C and −597G/A genotypes, sequence-specific primers were used for analysis of the DNA samples by polymerase chain reaction (PCR) (Applied Bio ProFlex Life Technologies, USA) [Table 2].
|Table 2: Sequence and specifications of primers used in polymerase chain reaction|
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After amplification of PCR, products were run on 2% agarose gel (Invitrogen) at 120 V for 45 min along with a Thermo Scientific Fisher 100-base pair DNA ladder. The gel was stained and observed SynGene Gel Doc System to note the position of the bands.
Sequencing was done through the standard technique of Sanger DNA sequencing using ABI 3500 genetic analyzer, 3500 (Applied Biosystems, Life Technologies, CA, USA). The sequencing results were read, and the SNP genotypes were identical.
All the patients were followed for 100 days to assess the status and outcome of the transplantation. Grading of aGVHD was carried out according to the standard Glucksberg scoring system I-IV.
Data were collected and analyzed using SPSS version 26 (IBM SPSS Statistics, Version 26, Chicago, USA). Descriptive statistics included mean ± standard deviation of continuous variables and frequencies of categorical variables. Comparison of frequencies between the groups was calculated using the Chi-square test, while independent-t-test and one-way ANOVA were carried out to compare the serum IL-6 levels among the groups.
| Results|| |
The mean patient age was 19.83 ± 12.58 years (range: 2–58). Males were 65 (63.7%) and females were 37 (36.3%), with a male-to-female ratio of 1.7:1. Different ethnicities were Punjabi (66, 64.7%), Pathan (22, 21.6%), Sindhi (4, 3.9%), Balochi (2, 1.9%), Gilgiti (4, (3.9%), and Kashmiri 4 (3.9%).
The genotypic frequency of −174G/C polymorphism in patients (GG: 28 [54.9%], GC: 16 [31.4%], and CC: 7 [13.7%]) was significantly different from those in donors (GG: 35 [68.6%], GC: 16 [31.4%], and CC: 0), P = 0.02. However, patients' genotype of homozygous GG and heterozygous GC was found to have significant correlation with aGVHD having with P = 0.001.
The frequency of polymorphism −597G/A was also identified in all the participants and the patient's genotype was found to be significantly associated with aGVHD with P = 0.04 [Table 4]. The donor genotype of −597G/A was not significantly related to aGVHD.
|Table 3: Outcome of allogeneic hematopoietic stem cell transplantation patients|
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|Table 4: Genotype frequencies of -174G/C and -597G/A in groups of acute graft-versus-host disease and nongraft-versus-host disease|
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The genotyping results were further validated by analyzing both SNPs on the genetic analyzer. The sequencing results were read, and the SNP genotypes were found to match the genotyping results.
Overall, although pretransplant IL-6 levels of patients and donors did not differ significantly (9.58 ± 5.9 pg/ml vs. 9.9 ± 8 pg/ml, P = 0.82), there was a significant difference between pre-and posttransplant IL-6 levels among patients (9.58 ± 5.9 pg/ml vs. 23.2 ± 20.2 pg/ml) with P < 0.0001. The posttransplant levels strongly correlated with the respective pretransplant levels in patients (rho = 0.801, P < 0.0001). Likewise, donor pretransplant and patient posttransplant IL-6 levels were also significantly different (9.90 ± 8 pg/ml vs. 23 ± 20.2 pg/ml, P < 0.0001). Patients with aGVHD had significantly high pretransplant levels compared to the non-GVHD group (14.4 ± 4.4 pg/ml vs. 4.5 ± 1 pg/ml) with P < 0.0001. Likewise, posttransplant IL-6 levels were also significantly high among aGVHD patients (39.8 ± 15 pg/ml) compared to the non-GVHD group (6.03 ± 1.2 pg/ml), P < 0.0001. Pre- and posttransplant IL-6 levels for different genotypes are compared in [Table 5].
|Table 5: Comparison of patient genotypes with pre- and posttransplant interleukin-6 levels within groups of acute graft-versus-host diseases and nongraft-versus-host disease|
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The recipients were followed up for a total of 100 days, and the survival status showed that 48 (94.1%) alive and 3 (5.9%) patients died. A total of 26 (51%) cases of aGVHD and 25 (49%) cases of non-GVHD were noted [Table 3]. The grading of aGVHD was done according to the standard criteria, as shown in [Table 6]. The multivariate analysis was also carried out for finding association of these SNPs with GVHD [Supplementary Table 1].
|Table 6: Comparison of single-nucleotide polymorphisms of-174G/C and-597G/A genotypes with acute graft-versus-host disease and grading of acute graft-versus-host disease cases|
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| Discussion|| |
aHSCT is a therapeutic modality for many malignant and nonmalignant hematological conditions. The therapeutic benefit of aHSCT is still restricted by complications such as GVHD, severe infections, and TRM. aGVHD is one of the main complications of transplantation, causing morbidity and mortality. Even with prophylactic management through immunosuppressive treatment, the development of aGVHD has been historically observed in 20%–80% of patients after aHSCT according to many studies.,,, aGVHD comprises a complicated pathology, developing in three diverse stages. It involves cellular stimulation and inflammatory cytokine production that, in turn, impact the levels of various ILs and other proteins in a recipient's blood. Although lately many investigators have focused on identifying markers related to prediction, early detection, and confirmation of aGVHD,,, still more work is needed for determination of appropriate markers and their genetic and epigenetic control,,, so that management of aGVHD patients with therapeutic drugs should be monitored by the use of reliable and sensitive analytical biomarkers acting as surrogate.
The SNPs in the IL-6 promoter region at position −174G/C and −597G/A affect the initiation of transcription, and certain genotypes have been shown to be associated with high transcriptional levels of IL-6 in relation to several autoimmune disorders and inflammatory illness in different studies.,,,,, In a previously available study, both the genotypes of patients and donors of IL-6 gene polymorphisms were studied as the risk predictors for kidney graft failure. In this study, the GG genotype was associated with successful kidney transplants, whereas the CC genotype was related to the failure of kidney transplants. The CC type was also found to have a strong association with liver transplant failure in a second study. Similarly, homozygous CC polymorphism of IL-6 gene has also been reported to be associated with bronchiolitis obliterans syndrome after lung transplantation.
The aim of our research project was to determine whether the −174G/C and −597G/A SNPs of IL-6 gene are linked to the incidence of aGVHD after aHSCT. Some of the studies reported only donor genotype of IL-6 polymorphism to be significantly associated with the incidence of the aGVHD. Their findings had no significance of patients' genotypes with the aGVHD.,, While other studies reported to have patients' genotype of IL-6 polymorphism to be significantly associated with the onset of aGVHD,,, which are similar to our findings of −597G/A genotyping in patients. A comparison of our findings with other studies is shown in [Supplementary Table 2].
We concluded that all the participants having G allele present in homozygous or heterozygous in −174G/C (GG = 53.8%, GC = 34.6%) and −597G/A (GG = 69.2%, GA = 15.4%) had a higher number of aGVHD cases and the highest frequency of grade II aGVHD. Our finding of GG and GC of −174G/C in both patients and donors all had the highest grade II aGVHD. The findings of GG of −597G/A in both recipients and donors had the highest number of grade II aGVHD cases, and the GA in recipients had the highest number of grade II–III aGVHD cases, while the donor GA had the highest number of grade I cases for aGVHD.
Other studies done by Kamel et al. in 2018, Tvedt et al. in 2017 and 2018, and Balavarca et al. in 2015 all showed no significance of the IL-6 polymorphism of either patients or donors with aGVHD. They concluded that the presence of G allele in homozygous or heterozygous types in either patients or donors was significantly associated with a higher risk of GVHD and an increased number of cases which are similar to our findings too.,,,
The presence of G allele of (-174G/C or -597G/A) in either recipients or donors is to be related and contributed in the development of aGVHD, and it has also shown to be associated with the high serum levels of IL-6 in healthy individual too. However, a higher number of cases of patients noted with aGVHD in those having G allele at -174G/C and -597G/A positions of IL-6 gene, and this association was also statistically significant like our findings too. aGVHD was found to be significant with gender compatibility, P < 0.001. Our findings were subjected to the cumulative analysis with the reports published by Cavet et al., Socié et al., Kamel et al., and Tvedt et al.,,,
We stated the findings of our project to determine the potential of serum IL-6 before and after the aHSCT in assessing aGVHD and survival after transplant and compared it with other studies done.,,, The results of IL-6 levels of our study also had a highly significant association between the two groups of aGVHD and non-GVHD cases with P < 0.0001. The IL-6 levels of both the pre- and posttransplant had very significant results, with the GG genotype of both the SNPs −174G/C and −597G/A having P < 0.0001. These results were like the above-mentioned studies. This shows that the increase in the IL-6 levels is due to the presence of the gene and high levels resulting in the pathophysiology of aGVHD and many other inflammatory diseases.,,,,
There are few previous studies done in Pakistan on the similar SNPs of −174G/C and −597G/A in different diseases such as rheumatoid arthritis, coronary heart disease, and dilated cardiomyopathy. All of these have shown a similar association of polymorphism and high IL-6 levels with the disease progression as compared to the controls [Supplementary Table 2] and [Supplementary Table 3].,,,
There are still limitations in the estimation of aGVHD, specifying the critical requirement for techniques and dependable blood tests of the laboratory to allow a personalized beneficial methodology. Recognizing these patients with highly risk of aGVHD at the time of transplantation may help in developing strict intensive care, better precautionary carefulness, and advancement in different and more actual immunosuppressive treatments prior to transplant.
| Conclusion|| |
We concluded that the two SNPs −174G/C and −597G/A of IL-6 either in donors or recipients predisposed to increase the risk of growth of aGVHD in aHSCT. We concluded the patient's genotype of −597G/A to be considerably correlated with the incidence of aGVHD, while the presence of G types (homozygous or heterozygous) in −174G/C and −597G/A in either patients or donors to be also significantly associated with aGVHD. The G genotype is found to be associated with high serum IL-6 in pre- and posttransplant levels to be significantly associated with the incidence of aGVHD.
IL-6 may increase the risk stratification of recipients at high danger for aGVHD and mortality, giving a space for further precautionary approaches given initially to improve the condition of life and consequence of aHSCT.
We recommend SNP evaluation in our transplant setting, which may help recognize high-risk recipients of aGVHD early in time and calculate the disease before its clinical signs appear.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]