Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation

Proinflammatory cytokines including interferon-gamma (IFN gamma), interfeuk in-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) are implicated in the pathogenesis of acute graft-versus-host disease (aGVHD). Cytokine gene polymorphism is associated with functional differences in cytokine regulati on and altered clinical performance in a variety of diseases. Polymorphism in the IFN gamma intron1 microsatellite (CA)(n) repeat has been linked with in vitro IFN gamma production and renal transplant rejection. The IL-6(-17 4)(G/C) single nucleotide polymorphism has been linked to in vitro and in v ivo IL-6 production, juvenile chronic arthritis, and renal transplant rejec tion. This study examined the potential association of GVHD with IFN gamma, and IL-6 polymorphisms in 80 sibling bone marrow transplant (BMT) donor/re cipient pairs. Patients homozygous for the IFN gamma Intron1 allele 3 had m ore severe (grade III-IV) aGVHD. Patients possessing the IL-6(-174)G allele had a trend toward higher grades of aGVHD, and those homozygous for the IL -6-174G allele were more likely to develop chronic GVHD (aGVHD). The associ ations of previously identified aGVHD severity-associated cytokine gene pol ymorphisms (TNFd and IL-10(-1064)) with severe aGVHD were reconfirmed. Logi stic regression analysis confirmed the association of severe aGVHD with rec ipient genotype at IFN gamma Intron1 (odds ratio [OR] 3.92; P =.02), IL-10- 1064 (OR 4.61; P =.026) and TNFd (OR 3,29; P =.039), and that of cGVHD with recipient IL-6-174 genotype (OR 4.25; P =.007), in addition to age, gender mismatch, and underlying disease. Assessment of cytokine genotype may pote ntially allow more accurate prediction of GVHD and appropriate adjustment o f GVHD prophylaxis, as well as indicating novel areas for future studies of GVHD pathogenesis. (C) 2001 by The American Society of Hematology.