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

Transplantation. 2006 Jan 27;81(2):247-54. doi: 10.1097/


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Amino Acid Substitution
  • Bone Marrow Transplantation / adverse effects
  • Bone Marrow Transplantation / mortality
  • Female
  • Gene Frequency
  • Graft vs Host Disease / etiology
  • Graft vs Host Disease / genetics*
  • Graft vs Host Disease / immunology*
  • Hematologic Neoplasms / genetics
  • Hematologic Neoplasms / immunology
  • Hematologic Neoplasms / therapy
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Hematopoietic Stem Cell Transplantation / mortality
  • Humans
  • Immunity, Innate / genetics
  • Infections / genetics
  • Infections / immunology
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Mutation
  • Nod2 Signaling Adaptor Protein
  • Retrospective Studies
  • Toll-Like Receptor 4 / genetics*
  • Transplantation, Homologous


  • Intracellular Signaling Peptides and Proteins
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • TLR4 protein, human
  • Toll-Like Receptor 4