Influence of βS-globin haplotypes hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia

Abstract

BackgroundSickle cell anemia is a chronic inflammatory disease characterized by an increased production of proinflammatory cytokines including tumor necrosis factor-alpha. Hydroxyurea, by decreasing the polymerization of hemoglobin, reduces inflammatory states. The effect of the genetic polymorphisms of sickle cell patients on tumor necrosis factor-alpha levels remains unknown.ObjectiveThe aim of this study was to investigate the association of tumor necrosis factor-alpha levels with β-globin haplotypes and the use of hydroxyurea.MethodsA cross-sectional study was performed of 67 patients with sickle cell anemia diagnosed at steady-state in a referral hospital in Fortaleza, Ceará, Brazil. A group of 26 healthy individuals was used as control. βS haplotype analysis was performed by restriction fragment length polymorphism-polymerase chain reaction. The tumor necrosis factor- alpha levels were measured by the enzyme-linked immunosorbent assay test. Laboratory data (complete blood count and fetal hemoglobin) and information regarding the use of hydroxyurea were obtained from medical records. Statistical analysis was performed using R software with the Kruskal-Wallis and Mann–Whitney tests. Statistical significance was established for p-values < 0.05 for all analyses.ResultsThe mean age of the participants was 35.48 years. Patients with sickle cell anemia had significantly higher tumor necrosis factor-alpha levels than controls (p-values < 0.0001). Tumor necrosis factor-alpha levels were lower in sickle cell anemia patients who were receiving hydroxyurea treatment than those who were not (p-value = 0.1249). Sickle cell anemia patients with Bantu/n genotype had significantly higher levels than patients with the Bantu/Benin genotype (p-value = 0.0021).ConclusionIn summary, βS-globin haplotypes, but not hydroxyurea therapy, have a role in modulating tumor necrosis factor-alpha levels in sickle cell anemia adults at steady-state. Many previous studies have investigated prognosis and inflammatory states in sickle cell anemia patients, but the discovery that tumor necrosis factor-alpha levels vary according to the genetic polymorphism of the patient is a new finding. © 2014 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. All rights reserved.

Sickle Cell Anemia Patients in Use of Hydroxyurea: Association between Polymorphisms in Genes Encoding Metabolizing Drug Enzymes and Laboratory Parameters

“…HU therapy was also observed to significantly reduce HbS levels, which is consistent with results by Shome et al who also found an association between HU use and significantly reduced HbS levels in SCA patients [ 38 ]. We also detected significantly higher HbF levels in SCA-HU + patients compared to controls, which confirms results in previous studies regarding the efficacy of HU in inducing HbF synthesis [ 3 , 34 , 39 , 40 ].…”

“…HU therapy was found to be associated with higher values of MCH and MCV, similar to what was shown by Pallis et al [ 34 ]. On the contrary, Laurentino et al did not observe significant differences in MCH and MCV levels among SCA-HU + and SCA-HU − patients [ 3 ]. The present study found an association between HU therapy and significant reductions in leukocyte, eosinophil, and monocyte counts, confirming its cytoreductive effect.…”

“…Sickle cell anemia (SCA) is a monogenic disease, characterized by clinical heterogeneity [ 1 ]. The clinical diversity of SCA patients has been attributed to several factors, such as sociodemographic, socioeconomic, environmental, and genetic factors [ 2 , 3 ]. Fetal hemoglobin (HbF: α 2 γ 2 ) is a classic genetic modulator associated with a less-severe SCA outcome, and high concentration of HbF inhibits the polymerization of the hemoglobin variant S (HbS) by formation of asymmetric hybrids with gamma ( γ ) chain and β S chain ( α 2 γβ S ) that present high affinity for oxygen [ 4 , 5 ].…”

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

“…Studies on the effect of HU treatment on plasma TNF-α level yielded controversial results [38,39]. In this study, HU treated patients had a high level of TNF-α.…”

Comment on “Influence of βS-globin haplotypes and hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia”✩✩See paper by Laurentino MR et al. on pages 121-5.

“…This important finding supports the association between pro-inflammatory cytokine release and the clinical severity of SCA as these cytokines induce adhesion molecule activity in the endothelium 18 . Moreover, Laurentino et al found higher TNF-α levels in individuals with the Bantu haplotype than those with the Benin haplotype 13 . These data not only reflect the severity of the diseases but also the effect of haplotypes in modulating the SCA phenotype.…”