The presence of -308A TNFα is associated with anemia and thrombocytopenia in patients with myelodysplastic syndromes

Belli, Carolina; Bestach, Yesica Soledad; Sieza, Yamila; Gelemur, Marta; Giunta, Mario; Flores, María Gabriela; Watman, Nora; Bengió, Raquel; Larripa, Irene

doi:10.1016/j.bcmd.2011.09.003

Cited by 6 publications

(5 citation statements)

References 31 publications

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“…Since our previous work was focused on only the TNF -308 G/A SNP, we increased the population size and extended the study to five other candidate polymorphisms in the IFNG, IL6, and TGFB1 genes based on published data that indicated the relevance of these cytokines to the MDS aberrant microenvironment. We were then able to confirm that the high-expressing TNF genotype (A/A + G/A) was related to an increased chance of developing MDS, in accord with other previous reports [23,35], and that this genotype was associated with anemia and thrombocytopenia at diagnosis [22]. Consistent with the cytopenia, these patients proved to be transfusion dependent and died of non-AML related causes.…”

Section: Discussionsupporting

confidence: 89%

“…Relevant MDS clinical variables were analyzed according the respective level of expression associated with each cytokine polymorphism (Online Resource Table S3). As we previously described [22], the presence of the genotype of high (G/A + A/ A) as opposed to low (G/G) TNF expression was associated with a lower hemoglobin level (8.8 vs. 9.7 g/dL; p = 0.034), reduced platelet counts (90,000 vs. 131,000/μL; p = 0.010), and a shorter TDFS (7.9 vs. 27.0 months; p = 0.016). In addition, this group ran a 3.…”

Section: Association Of Cytokine Polymorphisms With Clinical Variablesmentioning

confidence: 99%

“…Several reports have identified polymorphic variants in human leukocyte antigen genes and in cytokine and cytokinereceptor genes that are linked to susceptibility to cancer and autoimmunity and that contribute differentially to disease development, progression, and the response to therapy [17][18][19][20][21][22][23][24][25][26][27]. Functional variants such as single nucleotide polymorphisms (SNPs) localized in the promoter or regulatory regions of relevant cytokine genes may influence their genetic expression, thus skewing the functioning of immune cells through the action of their effector molecules, the cytokines and chemokines.…”

Section: Introductionmentioning

confidence: 99%

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Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Association Of Cytokine Polymorphisms With Clinical Variablesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes

et al. 2017

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Section: Resultsmentioning

confidence: 99%

“…Tumor Necrosis Factor alpha (TNF- α ) protein is a major regulatory cytokine that plays a role in many immune-mediated diseases and hematologic malignancies [ 38 ]. In MDS, the −308A TNF-α genetic polymorphism, which increases the transcription level of this inflammatory cytokine, was associated with MDS patients [ 38 ]. Overexpression of −308A TNF- α protein may also be responsible for promoting a proinflammatory state in benzene-exposed workers; one study showed that only the −238 TNF- α and not the −308A TNF- α polymorphism was significantly associated with the development of benzene-induced dysplasia and not with an increased risk of MDS [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm

Fedak

2015

BioMed Research International

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Information on polymorphisms, mutations, and epigenetic events has become increasingly important in our understanding of molecular mechanisms associated with exposures-disease outcomes. Molecular landscapes can be developed to illustrate the molecular characteristics for environmental carcinogens as well as associated disease outcomes, although comparison of these molecular landscapes can often be difficult to navigate. We developed a method to organize these molecular data that uses a weight-of-evidence approach to rank overlapping molecular events by relative importance for susceptibility to an exposure-disease paradigm. To illustrate the usefulness of this approach, we discuss the example of benzene as an environmental carcinogen and myelodysplastic syndrome (MDS) as a causative disease endpoint. Using this weight-of-evidence method, we found overlapping polymorphisms in the genes for the metabolic enzymes GST and NQO1, both of which may infer risk of benzene-induced MDS. Polymorphisms in the tumor suppressor gene, TP53, and the inflammatory cytokine gene, TNF-α, were also noted, albeit inferring opposing outcomes. The alleles identified in the DNA repair gene RAD51 indicated an increased risk for MDS in MDS patients and low blood cell counts in benzene-exposed workers. We propose the weight-of-evidence approach as a tool to assist in organizing the sea of emerging molecular data in exposure-disease paradigms.

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TNF-α −308 G>A polymorphism and risk of bone marrow failure syndrome: A meta-analysis

Chen

Zhu

et al. 2015

Gene

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The presence of -308A TNFα is associated with anemia and thrombocytopenia in patients with myelodysplastic syndromes

Cited by 6 publications

References 31 publications

Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes

Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes

Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm

TNF-α −308 G>A polymorphism and risk of bone marrow failure syndrome: A meta-analysis

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