Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation

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Abstract
We made the hypothesis that donor and recipient gene polymorphisms that drive the host response to microorganisms could be associated with infections after bone marrow transplantation (BMT). HLA-identical BMT was performed for patients with acute (n = 39) or chronic leukemia (n = 68). Genotyping was performed in 107 D/R DNA pairs for gene polymorphisms of cytokines (tumor necrosis factor-α [TNF-α] and TNF-β, interleukin-1 receptor antagonist [IL-1Ra], IL-6, and IL-10), adhesion molecules (CD31 and CD54), Fcγreceptors (FcγRIIa, IIIa, IIIb), mannose-binding lectin (MBL), and myeloperoxidase (MPO). First infection (overall) and first episodes of bacterial, viral, or invasive fungal infection were studied retrospectively for 180 days after BMT. Univariate and multivariate analyses, using death as a competing event, were performed to study risk factors. In multivariate analysis, first overall infections were increased in patients with the FcγRIIa R-131 genotype (hazard ratio [HR] = 1.92; P = .04), and severe bacterial infections were increased when the MPO donor genotype was AG or AA (HR = 2.16; P = .03). Viral and invasive fungal infections were not influenced by any genetic factor studied. Interestingly, we also found that (1) time to neutrophil recovery was shorter when donors were FcγRIIIb HNA-1a/HNA-1b (HR = 1.77; P = .002); (2) donor IL-1Ra (absence of IL-1RN*2) increased the risk for acute graft-versus-host disease (GVHD) (II-IV) (HR = 2.17; P = .017); and (3) recipient IL-10 (GG) and IL-1Ra genotypes increased the risk for chronic GVHD (P = .03 and P = .03, respectively). Finally, 180-day transplantation-related mortality rates were increased when donors were FcγRIIIb HNA-1a/HNA-1a or HNA-1b/HNA-1b (HR = 2.57; P = .05) and donor MPO genotype was AA (HR = 5.14; P = .004). In conclusion, donor and recipient gene polymorphisms are informative genetic risk factors for selecting donor/recipient pairs and could help in the understanding of mechanisms involved in host defenses of BM transplant recipients.