Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD

Abstract

Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n = 180) and validation sets (n = 88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P o0.0001) and donor genotypes of IL6 (rs1800797; P = 6.2 × 10 −4 ) and IFNG (rs2069727; P = 4.4 × 10 −4 ) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n = 74) vs high risk (scores 1-3; n = 106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P o 0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P = 0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease

“…In the light of their prior preclinical studies, their emergent clinical experience, and their recent observations, Alam and colleagues have suggested that specific donor IFNγ and IL6 SNP/genotypes correlate strongly with the risk of steroid refractory GvHD. 16 Our findings corroborate the observation that IFNγ and IL6 are critical to the development and progression of acute GvHD. In addition, the need to selectively block both IFNγR and IL6R to prevent and treat GvHD further supports the rationale for combining an anti-human IFNγR antibody with tocilizumab.…”

“…Previous reports have shown that ruxolitinib potently inhibits IL6R signaling, 9 that the anti-IL6R–blocking antibody tocilizumab reduces acute GvHD in allo-HSCT patients, 15 and that donor IFNG and IL6 single nucleotide polymorphisms correlate with gastrointestinal GvHD severity. 16 Together, these observations suggest that IFNγR and IL6R signaling critically mediate GvHD. To test this hypothesis, we performed allo-HSCT using Ifngr −/− T cells and anti-mouse IL6Rα antibody as described in Supplementary Figure 2 .…”

Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease

“…In the light of their prior preclinical studies, their emergent clinical experience, and their recent observations, Alam and colleagues have suggested that specific donor IFNγ and IL6 SNP/genotypes correlate strongly with the risk of steroid refractory GvHD. 16 Our findings corroborate the observation that IFNγ and IL6 are critical to the development and progression of acute GvHD. In addition, the need to selectively block both IFNγR and IL6R to prevent and treat GvHD further supports the rationale for combining an anti-human IFNγR antibody with tocilizumab.…”

“…Previous reports have shown that ruxolitinib potently inhibits IL6R signaling, 9 that the anti-IL6R–blocking antibody tocilizumab reduces acute GvHD in allo-HSCT patients, 15 and that donor IFNG and IL6 single nucleotide polymorphisms correlate with gastrointestinal GvHD severity. 16 Together, these observations suggest that IFNγR and IL6R signaling critically mediate GvHD. To test this hypothesis, we performed allo-HSCT using Ifngr −/− T cells and anti-mouse IL6Rα antibody as described in Supplementary Figure 2 .…”

Association of IFN‐γ polymorphisms with ankylosing spondylitis risk

“…25 Alam et al reported the significant interaction of IFNG rs2069727 with gastrointestinal GVHD. 26 In this study, However, the study scheduled by Gonsky et al reported that IFN-γ rs1861494 polymorphism could influence inflammatory bowel disease severity via its functional roles in IFN-γ gene methylation and protein secretion among Caucasian population. 19 The divergences might be attributed to the relative small sample size, different study populations and geographic regions, as well as the diverse aetiologies of the study diseases.…”

“…The study carried out by Li et al suggested that GG genotype of IFN‐γ rs2069727 polymorphism had apparently different distributions between case and control groups, and might confer increased risk of hepatocellular carcinoma 25 . Alam et al reported the significant interaction of IFNG rs2069727 with gastrointestinal GVHD 26 . In this study, we also examined the association between rs1861494 polymorphism and susceptibility to AS in the study population.…”

Investigation of TGFB1 −1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation

“…Smaller studies were unable to find any correlation between TGFB1 polymorphisms and HSCT outcome [33][34][35]. Large scale replication and validation studies were also unable to confirm any association between TGFB1 polymorphism and HSCT outcome (The International Histocompatibility Working Group [IHWG] for 1058 HSCT pairs [36], DISCOVeRY-BMT genome wide association study for 2888 HSCT recipients [37], or other studies [38,39]).…”

Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease

“…In the light of their prior preclinical studies, their emergent clinical experience, and their recent observations, Alam and colleagues have suggested that specific donor IFNγ and IL6 SNP/genotypes correlate strongly with the risk of steroid refractory GvHD. 16 Our findings corroborate the observation that IFNγ and IL6 are critical to the development and progression of acute GvHD. In addition, the need to selectively block both IFNγR and IL6R to prevent and treat GvHD further supports the rationale for combining an anti-human IFNγR antibody with tocilizumab.…”

“…Previous reports have shown that ruxolitinib potently inhibits IL6R signaling, 9 that the anti-IL6R–blocking antibody tocilizumab reduces acute GvHD in allo-HSCT patients, 15 and that donor IFNG and IL6 single nucleotide polymorphisms correlate with gastrointestinal GvHD severity. 16 Together, these observations suggest that IFNγR and IL6R signaling critically mediate GvHD. To test this hypothesis, we performed allo-HSCT using Ifngr −/− T cells and anti-mouse IL6Rα antibody as described in Supplementary Figure 2 .…”

Association of IFN‐γ polymorphisms with ankylosing spondylitis risk

“…25 Alam et al reported the significant interaction of IFNG rs2069727 with gastrointestinal GVHD. 26 In this study, However, the study scheduled by Gonsky et al reported that IFN-γ rs1861494 polymorphism could influence inflammatory bowel disease severity via its functional roles in IFN-γ gene methylation and protein secretion among Caucasian population. 19 The divergences might be attributed to the relative small sample size, different study populations and geographic regions, as well as the diverse aetiologies of the study diseases.…”

“…The study carried out by Li et al suggested that GG genotype of IFN‐γ rs2069727 polymorphism had apparently different distributions between case and control groups, and might confer increased risk of hepatocellular carcinoma 25 . Alam et al reported the significant interaction of IFNG rs2069727 with gastrointestinal GVHD 26 . In this study, we also examined the association between rs1861494 polymorphism and susceptibility to AS in the study population.…”

Investigation of TGFB1 −1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation

“…Smaller studies were unable to find any correlation between TGFB1 polymorphisms and HSCT outcome [33][34][35]. Large scale replication and validation studies were also unable to confirm any association between TGFB1 polymorphism and HSCT outcome (The International Histocompatibility Working Group [IHWG] for 1058 HSCT pairs [36], DISCOVeRY-BMT genome wide association study for 2888 HSCT recipients [37], or other studies [38,39]).…”

Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease

“…In the light of their prior preclinical studies, their emergent clinical experience, and their recent observations, Alam and colleagues have suggested that specific donor IFNγ and IL6 SNP/genotypes correlate strongly with the risk of steroid refractory GvHD. 16 Our findings corroborate the observation that IFNγ and IL6 are critical to the development and progression of acute GvHD. In addition, the need to selectively block both IFNγR and IL6R to prevent and treat GvHD further supports the rationale for combining an anti-human IFNγR antibody with tocilizumab.…”

“…Previous reports have shown that ruxolitinib potently inhibits IL6R signaling, 9 that the anti-IL6R–blocking antibody tocilizumab reduces acute GvHD in allo-HSCT patients, 15 and that donor IFNG and IL6 single nucleotide polymorphisms correlate with gastrointestinal GvHD severity. 16 Together, these observations suggest that IFNγR and IL6R signaling critically mediate GvHD. To test this hypothesis, we performed allo-HSCT using Ifngr −/− T cells and anti-mouse IL6Rα antibody as described in Supplementary Figure 2 .…”

Association of IFN‐γ polymorphisms with ankylosing spondylitis risk

“…25 Alam et al reported the significant interaction of IFNG rs2069727 with gastrointestinal GVHD. 26 In this study, However, the study scheduled by Gonsky et al reported that IFN-γ rs1861494 polymorphism could influence inflammatory bowel disease severity via its functional roles in IFN-γ gene methylation and protein secretion among Caucasian population. 19 The divergences might be attributed to the relative small sample size, different study populations and geographic regions, as well as the diverse aetiologies of the study diseases.…”

“…The study carried out by Li et al suggested that GG genotype of IFN‐γ rs2069727 polymorphism had apparently different distributions between case and control groups, and might confer increased risk of hepatocellular carcinoma 25 . Alam et al reported the significant interaction of IFNG rs2069727 with gastrointestinal GVHD 26 . In this study, we also examined the association between rs1861494 polymorphism and susceptibility to AS in the study population.…”

Investigation of TGFB1 −1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation

“…Smaller studies were unable to find any correlation between TGFB1 polymorphisms and HSCT outcome [33][34][35]. Large scale replication and validation studies were also unable to confirm any association between TGFB1 polymorphism and HSCT outcome (The International Histocompatibility Working Group [IHWG] for 1058 HSCT pairs [36], DISCOVeRY-BMT genome wide association study for 2888 HSCT recipients [37], or other studies [38,39]).…”