Single Nucleotide Polymorphisms in Thrombomodulin Gene Predict Mortality in Patients With Graft-vs-Host Disease
The pathophysiology of steroid refractoriness in graft-vs-host disease in allogeneic stem cell transplantation is not completely understood, although there is evidence that endothelial cell stress, which involves endothelial thrombomodulin, plays a role. In a study reported in the Journal of Clinical Oncology, Rachakonda et al found that single nucleotide polymorphisms (SNPs) in the THBD gene encoding endothelial thrombomodulin were associated with significantly increased risk of non–relapse-related mortality in patients undergoing allogeneic stem cell transplantation who developed graft-vs-host disease but did not predict risk of graft-vs-host disease.
Study Details
The study involved analysis of the association of nonrelapse mortality with seven SNPs in THBD (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. Alterations found to be associated with nonrelapse mortality were then investigated in a validation cohort of 321 patients.
Increased Nonrelapse Mortality
In the training cohort, an increased risk of nonrelapse mortality was associated with three of the SNPs: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. These polymorphisms were nonoverlapping and had frequencies of 5%, 2.3%, and 12.3%. Patients in the training cohort with one of the high-risk THBD genotypes (CC for rs1962, TT for rs1042579, or GG for rs1042580) accounted for 17.6% of the cohort and had significantly increased risk of nonrelapse mortality compared with patients with none of these genotypes (hazard ratio [HR] = 2.31, P = .002). In the validation cohort, frequencies of the high-risk genotypes were 2.8%, 3.0%, and 11.9%. Among the 19.3% of patients with one of these genotypes, nonrelapse mortality was significantly increased vs those with none (HR = 2.18, P = .006).
In both the training and validation cohorts, the predictive power of the single nucleotide polymorphisms was restricted to patients who developed acute graft-vs-host disease (HR = 3.03, P < .001; HR = 2.49, P = .009). In the combined cohorts, the high-risk polymorphisms were associated with significantly increased nonrelapse mortality in both graft-vs-host disease grade 1 to 2 and grade 3 to 4 subgroups, but were not predictive in patients without acute graft-vs-host disease.
No Effect on Risk of Graft-vs-Host Disease
In multivariable analysis adjusting for donor type, sex match, conditioning, age, and stem cell source, presence of one vs none of the high-risk genotypes was independently predictive of worse nonrelapse mortality in both the training and validation cohorts (HR = 2.12, P = .006; HR = 2.13, P = .009). However, the high-risk THBD genotypes did not predict incidence of acute grade 1 to 2 or grade 3 to 4 graft-vs-host disease.
The investigators concluded: “THBD [single nucleotide polymorphisms] predict mortality of manifest [graft-vs-host disease] but not the risk of acquiring [graft-vs-host disease], supporting the hypothesis that endothelial vulnerability contributes to [graft-vs-host disease] refractoriness.”
Thomas Luft, MD, PhD, Medizinische Klinik V, Heidelberg, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from the Helmholtz-Alliance on Immunotherapy of Cancer and Wilhelm Sander-Stiftung. The authors indicated no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
