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• W2533253897 abstract "Abstract Abstract 4369 Immunosuppressive therapy (IST) is one of the main treatment modalities for acquired aplastic anemia (AA). Approximately 70% of AA patients have been known to achieve clinical improvements with IST consisting of antithymocyte globulin (ATG) and cyclosporine. This remarkably high response rate supports us to tell the immunogenic pathophysiology of AA. Autoreactive cytotoxic T cells play a key role in this immunogenic pathogenesis of AA by working with myelosuppressive cytokines like interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNFα), and transforming growth factor beta (TGFβ), which induce apoptosis in hematopoietic stem cells, partially through the Fas-dependent pathway. The purpose of this study is to find out which single nucleotide polymorphisms (SNPs) in cytokine genes were relevant to the risk of AA and whether the relevant SNPs were associated with response to IST in AA patients. Between January 2000 and December 2008 84 patients were screened and 80 patients confirmed as having acquired AA by bone marrow biopsy, and 84 age- and sex-matched healthy controls were analyzed consecutively. We genotyped the polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene, which are known to be involved in T cell-mediated marrow destruction. We assessed the association between polymorphisms in those selected genes and risk for AA, and the association between those polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG -2353 T allele (dominant model, OR=0.43, p=.012) and TCA haplotype (dominant model, OR=0.50, p=.038) were significantly associated with the development of AA. In addition, this relevant IFNG -2353 T allele and TCA haplotype were related to the response of IST (dominant model, OR=0.076, p=.034). The presence of the minor T allele was protective and related to a 2.3-fold reduction in the risk for AA (p=.012), and the presence of the IFNG TCA haplotype was related to a 2-fold reduced risk for AA (p=.038). Concerning TGFB1, although its polymorphisms are not related to AA susceptibility, P10L T allele (recessive model, OR=0.18, p=.038) and CT haplotype (dominant model, OR=5.68, p=.038) were associated with response to IST. The T allele was related to a 4.3-fold reduced response to IST at 3 months (p=.038) and the presence of the CT haplotype was favorable to IST and was related to a 5.7-fold higher response at 3 months compared with the response in patients without the CT haplotype (p=.038). This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST. AA patients with intracellular IFN-γ expression in peripheral lymphocytes showed almost 3-fold higher response to IST than patients without IFN-γ-expressing lymphocytes (p<0.0001) and this finding puts weight on the immunogenic association of responsiveness. Regarding TGFβ, the functionality of polymorphisms and in TGFB1 has rarely been reported. However, the significant relationship between TGFB1 polymorphisms and therapeutic response to IST in our study suggests their late effects on marrow suppression. Our results may help explain the variability of response to IST in AA and suggests that patients with a high probability of response might be treated first with IST rather than conventional marrow transplantation.Table 1.Factors relevant to response to ISTFactorCorrected for Patient CharacteristicsUncorrected DataGenotypeOR (95% CI)POR (95% CI)PResponse at 3-month after IST (n=43) Age1.00 (0.96–1.05).841.02 (0.98–1.06).46 Sex (male vs female)1.13 (0.26–4.84).871.26 (0.37–4.23).71 Severity (severe vs non-severe)1.03 (0.23–4.53).0971.63 (0.48–5.47).43 TGFB P10L C/TTT vs CT + CC0.18 (0.03–0.90).0380.23 (0.06–0.95).043 TGFB haplotypeCT-CT + CT-other vs Other-other5.68 (1.11–29.15).0384.28 (1.05–17.42).043Response at 6-month after IST (n=43) Age1.00 (0.95–1.05).911.02 (0.97–1.06).45 Sex (male vs female)0.38 (0.072–2.01).250.60 (0.16–2.21).44 Severity (severe vs non-severe)2.53 (0.47–13.62).282.22 (0.59–8.26).24 IFNG -2353 A/TTT+AT vs AA0.076 (0.007–0.82).0340.40 (0.10–1.56).19 IFNG haplotypeTCA-TCA + TCA-other vs Other-other0.076 (0.007–0.82).0340.40 (0.10–1.56).19 TGFB haplotypeTC-TC vs TC-other + Other-other0.22 (0.05–0.90).0360.19 (0.03–1.09).063 Disclosures: No relevant conflicts of interest to declare." @default.
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• W2533253897 date "2011-11-18" @default.
• W2533253897 modified "2023-09-28" @default.
• W2533253897 title "Impact of Cytokine Gene Polymorphisms on Risk and Treatment Outcomes of Aplastic Anemia" @default.
• W2533253897 doi "https://doi.org/10.1182/blood.v118.21.4369.4369" @default.
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