Impact of Cytokine Gene Polymorphisms on Risk and Treatment Outcomes of Aplastic Anemia In Korea

Abstract

AbstractAbstract 4432 IntroductionThe clinical evidence of responsiveness to immunosuppressive therapy (IST) supports immune pathophysiology for acquired aplastic anemia (AA). Recent studies suggested that auto-reactive cytotoxic T-cells against hematopoietic cells play a key role in the pathogenesis of AA with various cytokines. The purpose of this study is to investigate whether single nucleotide polymorphisms (SNP) of cytokine genes are related to the risk of AA and, furthermore, the response to IST. MethodsWe analyzed 80 adult patients diagnosed as acquired AA. The 84 unrelated, age and sex matched healthy subjects served as a control group. In 3 cytokine genes (IFN-γ, TNF-α, TGF-β) and one FAS gene, we selected 10 polymorphisms on the basis of allelic frequency and the assumption of clinical relevance from previously reported associations. To assess the association between polymorphisms and risk of AA, we calculated statistical differences in allele, genotype, and haplotype distributions between patients and controls using chi-square test in 3 genetic models (dominant, recessive, and additive). For the association between polymorphisms and response to initial course of IST, we analyzed 44 patients who were treated with IST using a multivariate logistic regression model. ResultsAmong 10 SNPs in 4 genes, one SNP and one haplotype in IFN-γ gene were significantly associated with the development of AA: IFN-γ -2353A/T; the presence of the T allele in dominant model was protective and was related to a 2.3-fold reduction in the risk for AA (P =.012); the presence of the IFN-γ TCA haplotype was related to a two-fold reduced risk for AA (P =.038).The IFN-γ -2353 T allele was shown to be resistant to IST; the presence of T allele and TCA haplotype in IFN-γ gene (dominant model) was related to a 13.2-fold reduced hematologic response at 6 months following initial IST (P =.034). However, 4 SNPs and 2 haplotypes in TNF-α gene did not show any significant associations with the response at 3 and 6 months. In terms of 2 SNPs in TGF-β gene, TGF-β P10L T/C was independently related; the T allele (recessive model) was related to a 4.3-fold reduced response to IST at 3 months (P =.038). Accordingly, the response was related to the TGF-β haplotype; the TC haplotype homozygote (recessive model) was related to a 4.6-fold reduced response to IST at 6 months (P =.036); the presence of CT haplotype (dominant model) was favorable to IST and was related to a 5.7-fold higher response at 3 months than the absence of the CT haplotype (P =.038). ConclusionThis exploratory study found that the genetic polymorphism of IFN-γ was susceptible to the development of AA and was related to the hematologic response following initial IST. In case of TGF-β, the polymorphisms were related to the response to IST, though they were not be related to the disease susceptibility. Large studies with a prospective design are needed to better understand the determinants of risk of AA and responsiveness to IST. Disclosures:No relevant conflicts of interest to declare.