Patient interleukin-18 GCG haplotype associates with improved survival and decreased transplant-related mortality after unrelated-donor bone marrow transplantation.
Interleukin-18 (IL-18), a proinflammatory cytokine, is elevated in patients with acute graft-versus-host disease (aGVHD). IL-18 induces Th1 differentiation and cytotoxic T-lymphocyte function, both of which have been implicated in the pathogenesis of aGVHD. However, recent studies have shown that neutralization of IL-18 by antibodies leads to an increased risk of aGVHD-related mortality while administration of IL-18 significantly improved survival. We have genotyped a cohort of 157 patient/donor pairs undergoing unrelated donor bone marrow transplantation (BMT) for three polymorphisms recently identified in the promoter of the IL-18 gene: G-137C, C-607A and G-656T. Using phase software, three main haplotypes were reconstructed: GCG, CAT and GAT. We found no association between the occurrence of aGVHD and patient/donor haplotypes. The presence of the GCG haplotype in patients was associated with significantly decreased risk of transplant-related mortality at 100 d (23% in patients with GCG vs. 48% in patients without GCG, P < 0.01) and at 1 year (36% vs. 65%, P < 0.01). The presence of the GCG haplotype in patients was also associated with improved survival (57% vs. 32%, P < 0.01). Cox regression analysis showed that the presence of the GCG haplotype was associated with a twofold increased probability of survival. These data suggest that the IL-18 promoter GCG haplotype may influence survival after unrelated donor BMT without altering the risk of aGVHD.
Cardoso
Sandra M P
SM
Department of Pathology and Microbiology, University of Bristol, Homeopathic Hospital Site, Cotham, University Walk, Bristol BS8 1TD, UK. s.pinto-cardoso@bristol.ac.uk
DeFor
Todd E
TE
Tilley
Louise A
LA
Bidwell
Jeffrey L
JL
Weisdorf
Daniel J
DJ
MacMillan
Margaret L
ML
D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000401:mortality*; D005260:Female; D006239:Haplotypes; D006801:Humans; D016130:Immunophenotyping; D020382:Interleukin-18 / Q000235:genetics*; D019520:Living Donors; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012044:Regression Analysis; D012306:Risk; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D020382:Interleukin-18