title: Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease.
abstract: OBJECTIVE
  Steroid-refractory graft-versus-host disease (GVHD) is a major and often fatal complication after allogeneic stem-cell transplantation (alloSCT). Although the pathophysiology of steroid refractoriness is not fully understood, evidence is accumulating that endothelial cell stress is involved, and endothelial thrombomodulin (THBD) plays a role in this process. Here we assess whether single-nucleotide polymorphisms (SNPs) within the THBD gene predict outcome after alloSCT.
  
  
  METHODS
  Seven SNPs within the THBD gene were studied (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. The relevant genotypes were then validated in an independent cohort (n = 321).
  
  
  RESULTS
  In the training cohort, an increased risk of nonrelapse mortality (NRM) was associated with three of seven SNPs tested: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. When patients were divided into risk groups (one v no high-risk SNP), a strong correlation with NRM was observed (hazard ratio [HR], 2.31; 95% CI, 1.36 to 3.95; P = .002). More specifically, NRM was predicted by THBD SNPs in patients who later developed GVHD (HR, 3.03; 95% CI, 1.61 to 5.68; P < .001) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariable analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM. All findings could be reproduced in the validation cohort.
  
  
  CONCLUSIONS
  THBD SNPs predict mortality of manifest GVHD but not the risk of acquiring GVHD, supporting the hypothesis that endothelial vulnerability contributes to GVHD refractoriness.
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Sivaramakrishna P
authors.initials: SP
authors.lastname: Rachakonda
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Penack
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Blau
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Igor Wolfgang
authors.initials: IW
authors.lastname: Blau
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radujkovic
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Uharek
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Dreger
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Sivaramakrishna P. Rachakonda and Rajiv Kumar, German Cancer Research Centre; Sascha Dietrich, Aleksandar Radujkovic, Anthony D. Ho, Peter Dreger, and Thomas Luft, University of Heidelberg, Heidelberg; Olaf Penack, Olga Blau, Igor Wolfgang Blau, and Lutz Uharek, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin; and Berend Isermann, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. thomas.luft@med.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Luft
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D042702:Angiopoietin-2 / Q000097:blood; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006086:Graft vs Host Disease / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D018180:Thrombomodulin / Q000097:blood / Q000235:genetics*
chemical_list: D042702:Angiopoietin-2; D009566:Nitrates; D018180:Thrombomodulin