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Open Access Highly Accessed Research article

Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia

Danilo Grunig Humberto Silva14, Edis Belini Junior1, Gisele Cristine de Souza Carrocini1, Lidiane de Souza Torres1, Octávio Ricci Júnior2, Clarisse Lopes de Castro Lobo3, Claudia Regina Bonini-Domingos1 and Eduardo Alves de Almeida4*

Author Affiliations

1 Department of Biology, Hemoglobin and Hematologic Genetic Diseases Laboratory, Sao Paulo State University–UNESP, Sao Paulo, Brazil

2 Department of Medicine, Sao Jose do Rio Preto Medical School–FAMERP, Sao Paulo, Brazil

3 Hematological State Institute “Arthur de Siqueira Cavalcanti”–HEMORIO, Rio de Janeiro, Brazil

4 Department of Chemistry and Environmental Sciences, Sao Paulo State University–UNESP, Sao Paulo, Brazil

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BMC Medical Genetics 2013, 14:108  doi:10.1186/1471-2350-14-108

Published: 9 October 2013

Abstract

Background

Sickle cell anemia (SCA) presents a complex pathophysiology which can be affected by a number of modifying factors, including genetic and biochemical ones. In Brazil, there have been no studies verifying βS-haplotypes effect on oxidative stress parameters. This study evaluated βS-haplotypes and Hb F levels effects on oxidative stress markers and their relationship with hydroxyurea (HU) treatment in SCA patients.

Methods

The studied group was composed by 28 SCA patients. Thirteen of these patients were treated with HU and 15 of them were not. We used molecular methodology (PCR-RFLP) for hemoglobin S genotype confirmation and haplotypes identification. Biochemical parameters were measured using spectrophotometric methods (Thiobarbituric-acid-reactive substances and Trolox equivalent antioxidant capacity levels, catalase and GST activities) and plasma glutathione levels by High-performance liquid chromatography coupled to electrochemical detection.

Results

We found the highest frequency of Bantu haplotype (48.2%) which was followed by Benin (32.1%). We observed also the presence of Cameroon haplotype, rare in Brazilian population and 19.7% of atypical haplotypes. The protective Hb F effect was confirmed in SCA patients because these patients showed an increase in Hb F levels that resulted in a 41.3% decrease on the lipid peroxidation levels (r =−0.74, p=0.01). Other biochemical parameters have not shown differential expression according to patient’s haplotypes. Bantu haplotype presence was related to the highest lipid peroxidation levels in patients (p < 0,01), but it also conferred a differential response to HU treatment, raising Hb F levels in 52.6% (p = 0.03) when compared with the group with the same molecular profile without HU usage.

Conclusions

SCA patients with Bantu haplotype showed the worst oxidative status. However these patients also demonstrated a better response to the treatment with HU. Such treatment seems to have presented a “haplotype-dependent” pharmacological effect.

Keywords:
Hemoglobin S; Beta-S-gene cluster haplotypes; Oxidative stress; Antioxidant capacity