The impaired hematopoiesis in acquired aplastic anemia (AA) results from immune-mediated mechanisms. We characterized polymorphisms implicated in controlling type-1 cytokine production in 69 patients with AA. Our data suggest that the studied polymorphisms are not associated with susceptibility in the overall AA population. However, the presence of the higher expressing TNF - 308A allele was associated with younger age (p = 0.0297) and more profound neutropenia (p = 0.0312), and over-represented in patients with very severe AA (p = 0.0168). The higher producing IFNG 12 CA-repeat allele showed strong linkage disequilibrium with the + 874T allele, and was associated with a lower hemoglobin level (p = 0.0351). Also, the presence of at least one higher expressing variant was more frequent among patients responding to immunosuppressive treatment (p = 0.0519). Our findings suggest that the presence of higher expressing variants of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in AA patient genotypes could be related to clinical parameters, disease severity and therapy outcomes.

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Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (-308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (-174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/μL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)_IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.