Association Between TNF and TNF Receptor II Gene Polymorphisms and Acute Graft-Versus-Host Disease in Unrelated Donor Allogeneic Haematopoietic Stem Cell Transplantation within Chinese Population.

The importance of theTumor Necrosis Factor (TNF), including TNF-αa and TNF-β, in both the initial preconditioning and effector phases of aGVHD is well established. TNF and TNF receptor II (TNFRII) gene contains multiple single nucleotide polymorphisms (SNPs) in the promoter and transcription start site. There are conflicting datas regarding the cytokines gene polymorphisms and the risk of aGVHD in several studies and no data about Chinese population. This present study was designed to test association of TNFA, TNFB and TNFRII genotype for gene polymorphisms of both donors and recipients with incidence and severity of aGVHD in HLA-matched unrelated allo-HSCT within Chinese population.

A total of 138 unrelated donor/recipient pairs, who had undergone HLA-matched allo-HSCT from January 2001 to March 2009 at the First Affiliated Hospital of Zhejiang University School of Medicine, were tested for TNFA (TNFαa-857 C>T,TNFαa-863 C>A,TNFαa-1031 T>C), TNFB (TNFβ+252 A>G) and TNFRII (codon 196 T>G) polymorphism allele frequencies and genotype. SNPs were analyzed by Multiplex Snapshot.

(1) The TNFαa-857 C/C genotype of the donor or recipient was significantly associated with a higher risk of aGVHD (for donor type:75.7% vs 41.9%, P=0.001; for recipient type: 72.7% vs 50.0%, P=0.039) and a higher incidence of grade II-IV aGVHD( for donor type:50.5% vs 19.4%, P=0.002; for recipient type:48.2% vs 25.0%, P=0.033). (2) The TNFβ+252*G allele of the donor or recipient was significantly associated with a higher incidence of aGVHD (for donor type:74.5% vs 46.9%, P=0.005; for recipient type: 75.0% vs 47.1%, P=0.005); (3) The TNFRII196 T/T genotype of the donor or recipient was significantly associated with a higher incidence of aGVHD (for donor type:73.7% vs 53.8%, P=0.028; for recipient type: 73.3% vs 58.3%, P=0.086); (4) TNF and TNFRII geng polymorphic features, together with other clinical and biological factor (patient's age, donor-recipient gender, diagnosis, conditioning regimen, transplant material and GVHD prophylaxis), were subjected to multivariate analysis for aGVHD manifestation in order to exclude indirect association of gene polymorphic features. In multivariate analysis, donor-recipient gender (female to male) (RR=1.602,95%CI: 1.035-2.479, P=0.034), the TNFαa-857 C/C genotype of donor (RR=2.177, 95%CI: 1.204-3.938, P=0.01) and the TNFβ+252*G allele of recipient (RR=1.920, 95%CI: 1.116-3.304, P=0.018) were found to significantly contribute to the development of aGVHD. The TNFαa-857C/C genotype of donor (RR=3.211, 95%CI: 1.373-7.509, P=0.007) and the TNFβ+252*G allele of recipient (RR=2.174, 95%CI: 1.063-4.443, P=0.033) were also associated with a higher incidence of grade II-IV aGVHD; (5) The genotypes of TNFαa-863 and TNFαa-1031 were not found to be associated with the risk of aGVHD.

These results, which is the first report of TNF and TNF receptor polymorphic features of Chinese population with the risk of aGVHD, suggest an interaction of the donor and recipient TNFαa-857, TNFβ+252 and TNFRII196 genotypes on risk of aGVHD. These results are helpful for predict allo-HSCT outcome, identify more suitable donors and clarify therapy on an individual patient basis.

No relevant conflicts of interest to declare.