Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation.
BACKGROUND
NOD2 and TLR-4 genes belong to the innate immune system that detects invading pathogens through several pattern-recognition receptors. Here we analyzed 403 patients for NOD2 gene mutations and 307 patients for TLR-4 gene mutations (Thr399Ile) with their respective donors and correlated the results with the incidence of acute graft-versus-host disease (aGVHD), severe acute GVHD (saGVHD), the risk for transplant-related mortality (TRM), overall survival (OS) and incidence of infectious complications.


METHODS
We performed a retrospective single-center study. Genotyping of TLR-4 and NOD2 were evaluated by real-time polymerase chain reaction.


RESULTS
Surprisingly, we found a significant reduced incidence of aGVHD, saGVHD, and intestinal GVHD for patients with NOD2 gene mutations on the donor side with 50%, 0% and 2% compared to patients with the wild-type NOD2 gene with 65%, 17%, and 26%, respectively (P<0.02). However, the incidence of saGVHD increased in patients with NOD2 mutations on the patient and donor (P/D) side with 44% versus 17% compared to patients with the wild-type gene (P<0.03). TLR-4 gene mutations at P/D side had an increased risk for saGVHD with 42% versus 15% of patients with wild-type gene (P<0.04). OS, TRM, and incidence of infectious complications were not influenced by the mutated genes. Multivariate analysis confirmed that NOD2 gene mutations on the donor side had a reduced risk for saGVHD (P<0.001), whereas mutations of the NOD2 gene on P/D side had an increased risk for saGVHD (P<0.01) in our analysis.


CONCLUSIONS
These results suggest that NOD2 mutations have influence on the occurrence of acute GVHD after transplantation.
Elmaagacli
Ahmet H
AH
Department of Bone Marrow Transplantation, University Hospital of Essen, Essen, Germany. ahmet.elmaagacli@uni-essen.de
Koldehoff
Michael
M
Hindahl
Heidrun
H
Steckel
Nina K
NK
Trenschel
Rudolf
R
Peceny
Rudolf
R
Ottinger
Hellmut
H
Rath
Peter-Michael
PM
Ross
Rudolf Stefan
RS
Roggendorf
Michael
M
Grosse-Wilde
Hans
H
Beelen
Dietrich W
DW
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000401:mortality; D005260:Female; D005787:Gene Frequency; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007239:Infections / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D012189:Retrospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014184:Transplantation, Homologous
D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4