Fcγ receptor type IIIA (FCGR3A) has a functional single-nucleotide polymorphism (rs396991), at which a G-to T-point mutation results in an amino acid substitution at position 158 (valine to phenylalanine; V158F). This study examined the effect of the FCGR3A polymorphism in donors and recipients on the clinical outcomes in unrelated HLA fully matched myeloablative BMT. The FCGR3A-V158F genotype was retrospectively analyzed in a total of 99 recipients with myeloid malignancies, and their unrelated donors. The presence of the 158V genotype in recipients showed a statistically better OS (adjusted hazard ratio (HR) 0.49; 95% confidence interval (CI) 0.26–0.93; P=0.03) and TRM (HR 0.30; 95% CI 0.14–0.67; P=0.003) without significant influence on the relapse rate. The recipient 158V genotype was also associated with a significantly reduced risk of chronic GVHD (HR 0.45; 95% CI 0.20–0.99; P=0.049) and a trend toward a reduced risk of grade II–IV acute GVHD (HR 0.55; 95% CI 0.27–1.10; P=0.09), leading to a significantly reduced GVHD-related mortality (HR 0.22; 95% CI 0.06–0.77; P=0.02). The donor FCGR3A polymorphism did not have any effect on the transplant outcomes. These results suggest an association between the recipient FCGR3A genotype and the clinical outcomes after BMT.
Hematopoietic SCT is a potentially curative therapy in a range of malignant and nonmalignant diseases. However, its utility is limited because of transplant-related life-threatening complications, including GVHD, infections and disease relapse.1 Although HLA matching represents the major genetic determinant in clinical outcome after allo-SCT, recent evidence suggests that non-HLA immune-associated genes are also implicated.2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs) that effect individual immune response to infections and inflammatory reactions are associated with transplant outcomes.3, 4, 5, 6, 7, 8, 9
Fcγ receptor type IIIA (FCGR3A), a low-affinity receptor capable of interaction with complexed or monomeric IgG, is expressed on neutrophils, eosinophils, natural killer cells, macrophages, monocytes, DC, γδ-positive T cells and keratinocytes.10, 11, 12, 13 FCGR3A mediates Ab-dependent cell-mediated cytotoxicity, phagocytosis, cytokine production and regulation of Ig production. FCGR3A has a functional SNP (rs396991), at which a G-to-T point mutation results in an amino acid substitution at position 158 (valine to phenylalanine; V158F) in the second Ig-like domain.14 The cells bearing the FCGR3A-158V genotype show a higher affinity for IgG1 and IgG3 than those without 158V, and are capable of binding IgG4,15 and thus can exert Ab-dependent cell-mediated cytotoxicity more efficiently.16 The 158V genotype is associated with susceptibility to rheumatoid arthritis17 and immune-mediated thrombocytopenic purpura,18 better clinical response to rituximab in B-cell lymphomas19, 20 and a lower risk of recurrent periodontitis.21 In contrast, systemic lupus erythematosus and better clinical outcome of cetuximab against metastatic colorectal cancer correlates with the 158F genotype.22, 23 This study analyzed the effect of donor and recipient SNP (rs396991) in the FCGR3A gene on the clinical outcomes in patients after allogeneic myeloablative BMT using an HLA allele-matched unrelated donor. The data show that the presence of the FCGR3A-158V genotype in the recipient was associated with significantly better transplant outcomes on the OS, TRM and GVHD.
Patients and methods
FCGR3A genotyping was performed on a total of 99 recipients with myeloid malignancies and their unrelated donors who underwent transplantation after myeloablative conditioning through the JMDP (Japan Marrow Donor Program) with T-cell-replete marrow from an HLA-A, -B, -C and -DRB1 allele-matched donor between November 1995 and March 2000. HLA genotypes of HLA-A, -B, -C and -DRB1 allele of patient and donor were determined by the Luminex microbead method described previously (Luminex 100 System; Luminex, Austin, TX, USA).24, 25 No patient had a history of any previous transplantation. The final clinical survey of these patients was completed by 1 November 2007. Diagnoses were AML in 47 (47%), CML in 42 (42%) and myelodysplastic syndrome in 10 patients (10%; Table 1). The recipients were defined as having standard risk disease if they had AML in first CR, CML in any chronic phase or myelodysplastic syndrome. All others were designated as high-risk disease. CYA- or tacrolimus-based regimens were used in all patients for GVHD prophylaxis, and anti-T-cell therapy, such as antithymocyte globulin and ex vivo T-cell depletion, was not. All patients and donors gave their written informed consent to participate in molecular studies of this nature according to the declaration of Helsinki at the time of transplantation. The project was approved by the institutional review board of Kanazawa University Graduate School of Medicine and JMDP.
FCGR3A rs3969913 genotyping
Genotyping of FCGR3A was performed using the TaqMan-Allelic discrimination method26 with a 7900-HT Real Time PCR system (Applied Biosystems, Foster City, CA, USA), and results were analyzed using the Allelic Discrimination software program (Applied Biosystems). The genotyping assay was conducted in 96-well PCR plates. The amplification reaction contained template DNA, the TaqMan universal master mix and the specific probe rs396991 designed for SNP of FCGR3A (product No C_25815666_10; Applied Biosystems).
Data management and statistic analysis
Data were collected by the JMDP using a standardized report form. Follow-up reports were submitted at 100 days, 1 year and annually after transplantation. The pre-transplant CMV serostatus was routinely tested only for patients but not for their donors. Engraftment was confirmed by an ANC of >0.5 × 109/L for at least 3 consecutive days. Acute and chronic GVHD were diagnosed and graded using established criteria.27, 28 The OS was defined as the number of days from transplantation to death from any cause. Disease relapse was defined as the number of days from transplantation to disease relapse. TRM was defined as death without relapse. Any patients who were alive at the last-follow-up date were censored. The data on the causative microbes of infections, post-mortem changes in the cause of death and staging of acute GVHD, as well as the data on supportive care including infection prophylaxis and therapy of GVHD, which were given on institution basis, were not available in this cohort. The analysis was performed using the Excel 2007 (Microsoft Corp., Redmond, WA, USA), OriginPro version 8.0J (Lightstone Inc., Tokyo, Japan) and R (The R Foundation for Statistical Computing, Perugia, Italy) software programs.29 The probability of OS was calculated using the Kaplan–Meier method and compared using the log-rank test. The probabilities of TRM, disease relapse, acute GVHD, chronic GVHD and each cause of death were compared using the Grey test30 and analyzed using the cumulative incidence analysis,29 considering relapse, death without disease relapse, death without acute GVHD, death without chronic GVHD and death without each cause as respective competing risks. The variables included the recipient age at the time of transplantation, sex, CMV serostatus before transplantation, disease characteristic (disease type and disease risk at transplantation), donor characteristics (age, sex, sex compatibility and ABO compatibility), transplant characteristics (TBI-containing regimen, tacrolimus vs CYA and total nucleated cell count harvested per recipient weight). The median values were used as the cutoff point for continuous variables. The χ2 test and Mann–Whitney test were used to compare two groups. The Hardy–Weinberg equilibrium for the FCGR3A gene polymorphism was tested using the Haploview program.5 Multivariate Cox models were used to evaluate the hazard ratio (HR) associated with the FCGR3A polymorphism. Covariates found to be significant in univariate analyses (P⩽0.10) were included in the models. The P-values were two sided and outcomes were considered to be significant with P⩽0.05 in both the univariate and multivariate analyses.
Frequencies of the FCGR3A genotyping
The FCGR3A gene polymorphism (rs396991) was analyzed in 99 unrelated BM donor-myeloablative transplant recipient pairs (Table 1). The genotype frequencies of 158V/V, 158V/F and 158F/F were 4, 42 and 54% in donors, and 3, 41 and 56% in recipients. These were similar to a previous report14, 31 in Japanese populations and were in accord with the Hardy–Weinberg equilibrium (P=0.91).
Transplant outcome according to the FCGR3A genotype
The median follow-up duration in the cohort was 109 months among the survivors (range 43–134 months), and 16 recipients (16%) had relapsed or progressed and 47 (47%) had died. Three patients (3%) died before undergoing engraftment.
The transplant outcomes according to the FCGR3A genotype are summarized in Table 2. The recipient 158V genotype was associated with a significantly reduced incidence of GVHD-related mortality (7 vs 25%, P=0.01; Figure 1b), and a trend toward a reduced incidence of chronic GVHD (33 vs 45%, P=0.07) and reduced 5-year TRM (22 vs 40%, P=0.07; Figure 1a). The donor genotype had no significant effects on the transplant outcomes.
All factors that were found to be significant in univariate analyses were included in the model. The presence of the 158V genotype in recipients were statistically significant in the multivariate analyses for better OS (HR 0.49; 95% confidence interval (CI) 0.26–0.93; P=0.03; Table 3) and TRM (HR 0.30; 95% CI 0.14–0.67; P=0.003). In addition, the recipient 158V genotype was associated with a significantly reduced incidence of chronic GVHD (HR 0.45; 95% CI 0.20–0.99; P=0.049) and a trend toward a lower incidence of grade II–IV acute GVHD (HR 0.55; 95% CI 0.27–1.10; P=0.09), resulting in a significantly reduced GVHD-related mortality (HR 0.22; 95% CI 0.06–0.77; P=0.02). A correlation between the recipient 158V genotype and low infection-related death was also observed (HR 0.42; 95% CI 0.17–1.01; P=0.05). The donor 158V genotype did not significantly influence the transplant outcomes.
This study showed a considerable effect of the recipient FCGR3A-158V genotype on GVHD development and GVHD-related mortality, thus positively contributing to a significantly better TRM and OS for patients with myeloid malignancies receiving HLA-matched myeloablative BMT. The presence of 158V in recipients did not influence disease relapse. Therefore, recipients with the 158V genotype may be capable of avoiding GVHD without compromising a GVL effect. The recipient 158V genotype also showed a trend toward reduced infection-related mortality, which might result from a reduced need for immunosuppressive therapy due to a low incidence of GVHD, although the data regarding treatment for GVHD were unavailable in this cohort. This is the first report to show that the FCGR3A-V158F polymorphism influences transplant outcomes.
Little is known about the involvement of FCGR3A in the pathogenesis of GVHD. Indirect evidence in animal and human studies showed that B cells have an important role in the immunopathophysiology of acute and chronic GVHD,12, 32, 33, 34, 35 in which FCGR3A is involved through Ab-mediated immune responses, including Ab-dependent cell-mediated cytotoxicity and FCGR3A-mediated endocytosis. Previous reports showing the effectiveness of B-cell depletion in the treatment of acute33 and chronic GVHD35 prompted a working hypothesis that the presence of the FCGR3A-158V genotype, which potentially mediates Ab-dependent cell-mediated cytotoxicity more efficiently in comparison to its absence,16 may be a risk factor contributing to the development of acute and chronic GVHD. However, the current results contradict this hypothesis. One explanation of this conflict may be observed in reports that B-cell-deficient mice experience more exacerbated acute GVHD than wild-type mice,36 and that a high number of B-cell progenitors in the stem cell graft or in patients after allo-SCT is associated with a significantly lower rate of acute and chronic GVHD.37, 38 A study in HIV-infected men showed the presence of the FCGR3A-158V genotype to be associated with susceptibility to Kaposi's sarcoma and human herpesvirus-8 infection,39 thus suggesting that the 158V genotype may possess an immunologically recessive nature in immunocompromised patients similar to transplant recipients. However, precisely how the recipient FCGR3A polymorphism influences the pathophysiology of GVHD is still unknown. The first assumption is that in the light of the pathogenesis of GVHD,40, 41 differential binding of IgG to FCGR3A on recipient DCs might alter downstream events, such as the release of cytokines or chemokines, which consecutively could influence pathway essential for the development of GVHD. The second assumption is that the expression of FCGR3A on keratinocytes42 may have a role in neutralizing the autoantibodies contributing to GVHD.
An alternative explanation is that the association between the recipient FCGR3A polymorphism and the transplant outcomes could develop from polymorphisms in other genes in linkage disequilibrium with the FCGR3A gene. One possible candidate is the Fcγ receptor IIA (FCGR2A) H131R polymorphism shown to be in linkage disequilibrium with the FCGR3A polymorphism in the Caucasian populations.31, 43 However, the absence of a linkage disequilibrium between FCGR3A and FCGR2A genes in Japanese population31 suggests that the FCGR3A polymorphism is more likely responsible for the transplant outcomes.
The current data are not consistent with a previous French study44 that found no significant association between the FCGR3A-V158F SNP polymorphism and transplant outcomes. One of the reasons for this discrepancy may be that the population in the initial study included only HLA-identical sibling BMT recipients and was not stratified into myeloid and lymphoid malignancies to examine the effect of gene polymorphism on transplant outcomes. There is a possibility that the influence of the FCGR3A polymorphism is restricted exclusively to unrelated BMT and myeloid malignancies. Alternatively, these conflicting findings may result from ethnic differences in the study population. Verification of the present data in other cohorts has still to be made so that the implications of the findings can be fully accepted.
This study suggests that the genotyping of FCGR3A in transplant recipients before transplantation may provide a recipient bearing the 158F/F genotype an opportunity to avoid the risk of GVHD by favoring a BM or cord blood, and an HLA-matched graft, and planning more immunosuppressive regimens. Further studies are required to ascertain whether the findings of this study can be extended to other disease groups or other stem sources or HLA-mismatched transplantation.
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We are indebted to Drs Hiroko Oshima, Masanobu Oshima and Atsushi Hirao, Ms Kayoko Yamada, Mayu Yamada and Yuki Motohashi at Kanazawa University, and Dr Keitaro Matsuo at Aichi Cancer Center Research Institute for their technical assistance. We thank all the Japan Marrow Donor Program (JMDP) transplant teams who have contributed patients and donors to this study. This study was supported by grants from the Ministry of Health, Labor and Welfare, and the Ministry of Education, Culture, Sports and Technology, and Funds from the Mitani Research and Development Assistance Organization (Kanazawa, Japan) and by the Japan Leukemia Research Fund (Tokyo, Japan).
The authors declare no conflict of interest.
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Takami, A., Espinoza, J., Onizuka, M. et al. A single-nucleotide polymorphism of the Fcγ receptor type IIIA gene in the recipient predicts transplant outcomes after HLA fully matched unrelated BMT for myeloid malignancies. Bone Marrow Transplant 46, 238–243 (2011). https://doi.org/10.1038/bmt.2010.88
- unrelated donor
- single-nucleotide polymorphism
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