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.
Department of Pathology and Microbiology, University of Bristol, Homeopathic Hospital Site, Cotham, University Walk, Bristol BS8 1TD, UK. s.pinto-cardoso@bristol.ac.uk
Sandra M P
SM
Cardoso
Todd E
TE
DeFor
Louise A
LA
Tilley
Jeffrey L
JL
Bidwell
Daniel J
DJ
Weisdorf
Margaret L
ML
MacMillan
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