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

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Abstract

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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Acknowledgements

The authors would like to thank all members of Argentine participating hematological services for their involvement in the present study. All the authors gave significant intellectual contributions to the composition of the manuscript, critically reviewed the content, and approved the final version.

This paper was supported by Argentine grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) (PIP 0088 and PIP 0056) and the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) (PICT 1677 and PID 0044).

Dr. Donald F. Haggerty, a retired academic career investigator and native English speaker, edited the final version of the manuscript.

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Authors and Affiliations

  1. Laboratorio de Genética Hematológica, Instituto de Medicina Experimental (IMEX-CONICET)/ Academia Nacional de Medicina (ANM), Pacheco de Melo 3081, CP 1425, Ciudad Autónoma de Buenos Aires, Argentina

    Yesica Bestach, Virginia Palau Nagore, Irene Larripa & Carolina Belli

  2. Servicio de Hematología, Hospital General de Agudos “C.G. Durand”, Ciudad Autónoma de Buenos Aires, Argentina

    María G. Flores & Jacqueline González

  3. Servicio de Hematología, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina

    Jorge Arbelbide

  4. Servicio de Hematología, Hospital General de Agudos “J.M. Ramos Mejía”, Ciudad Autónoma de Buenos Aires, Argentina

    Nora Watman

  5. Servicio de Hematología, Hospital Interzonal General de Agudos “Gral. San Martín”, La Plata, Buenos Aires, Argentina

    Yamila Sieza

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  1. Yesica Bestach
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  2. Virginia Palau Nagore
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  3. María G. Flores
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  7. Yamila Sieza
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  8. Irene Larripa
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  9. Carolina Belli
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Correspondence to Yesica Bestach.

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The ethics committee of the Institutos de la Academia Nacional de Medicina has evaluated and approved this research. Since this investigation is a retrospective and prospective study; therefore, a formal consent was required in the last cases.

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The authors declare that they have no conflict of interest.

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Bestach, Y., Nagore, V.P., Flores, M.G. et al. Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes. Ann Hematol 96, 1287–1295 (2017). https://doi.org/10.1007/s00277-017-3036-4

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  • DOI: https://doi.org/10.1007/s00277-017-3036-4

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