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The Presence of -308A TNF Allele is Associated with Clinical Parameters of Myelodysplastic Syndromes (pp. 75-92) $100.00
Authors:  (Yesica Bestach, Mar¨ªa G. Flores, Francisco Sakamoto, Raquel Bengi¨®, Irene Larripa, Carolina B. Belli, Laboratorio de Gen¨¦tica Hematol¨®gica, Instituto de Medicina Experimental (IMEX-CONICET)/ Academia Nacional de Medicina (ANM), Buenos Aires, Argentina, and others)
Abstract:
Cytokines play important roles in the regulation of hematopoiesis,
and a fine balance between the actions of stimulatory/ myelosuppressive
factors is required for optimal production of cells of different
hematopoietic lineages. Tumor Necrosis Factor-alpha (TNF ) is a
multifunctional proinflammatory cytokine that has been shown to
strongly inhibit hematopoiesis and has been implicated in the
pathogenesis and phenotypes of Myelodysplastic Syndromes (MDS).
MDS are a heterogeneous group of clonal hematopoietic stem cell
disorders characterized by ineffective hematopoiesis, multilineage
dysplasia, peripheral cytopenia(s), and susceptibility to leukemia. The
phenotypic diversity of MDS may be the consequence of a dynamic
balance among the marrow microenvironment, proliferation capacity of
the abnormal clone and intensity of the immune attack towards the
marrow. The ineffective hematopoiesis is accompanied by an extensive
apoptotic cellular death of myeloid precursors at the beginning of the
disease. The bone marrow microenvironment may interact with MDS
clone to create an adverse proinflammatory cytokine background
associated with increased apoptotic levels. However, molecular
mechanisms involved in this aberrant cytokine generation are not known.
The regulatory and coding regions of cytokine genes are relatively
polymorphic including a significant number of single nucleotide
polymorphisms (SNPs), some of which are known to modify cytokine
activity. TNF gene, located at 6p21.3, contains in its promoter region the
-308G/A SNP and the -308A variant has been associated with an
increased transcription and production of this cytokine. Therefore, the
aim of our work was to study the -308G/A TNF SNP and to analyze
whether the presence of the high producing variant is associated with
clinical parameters in a cohort of 132 Argentine de novo MDS patients.
We found that the A/A+G/A genotype was overrepresented 2-fold in our
population (p=0.020, odds ratio-OR: 2.122) and these differences were
more evident in the refractory anemia subtype (p=0.004, OR: 2.855). The
presence of the high expressing -308A allele was associated with younger
age (57 ± 17 vs. 65 ± 14 years, p=0.017), higher risk to present with
hemoglobin levels less than 7g/dL (29% vs. 8%, p=0.002, OR: 4.688)
and platelet counts less than 50000/μL (38% vs. 18%, p=0.021, OR:
2.788) at diagnosis. Also, these patients showed 3.2-fold higher risk of
transfusion requirement (77% vs. 52%, p=0.012, OR: 3.205) during the
follow up.
In conclusion, the presence of an inherited -308A TNF, which
increases the transcription level of this proinflammatory cytokine, was
associated with more profound cytopenias and the necessity of
transfusion requirement in our cohort of MDS patients. This immunogenetic background may influence the bone marrow
microenviroment that cooperates with intrinsic defects of MDS
progenitors to increase the severity of certain phenotypic features of the
disease. 


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The Presence of -308A TNF Allele is Associated with Clinical Parameters of Myelodysplastic Syndromes (pp. 75-92)