Sickle Cell Anemia: Variants in the CYP2D6, CAT, and SLC14A1 Genes Are Associated With Improved Hydroxyurea Response

Abstract

Differences in hydroxyurea response in sickle cell anemia may arise due to a series of factors with genetic factors appearing to be predominant. This study aims to investigate the effects of single nucleotide polymorphisms in genes encoding drug-metabolizing enzymes and solute carriers on hydroxyurea response, in patients with sickle cell anemia. For that purpose, a total number of 90 patients with sickle cell anemia were recruited, 45 were undergoing hydroxyurea treatment, while 45 were not under the treatment. Association analyses were performed between CYP3A4 (rs2740574), CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and laboratory parameters. According to our findings, patients with hydroxyurea treatment demonstrated higher HbF levels and a significant improvement in hemolytic, hepatic, inflammatory, and lipid parameters in comparison to those without the treatment. We also found significant associations between the CYP2D6 (rs3892097), CAT (rs7943316 and rs1001179), and SLC14A1 (rs2298720) variants and an improvement of the therapeutic effects, specifically the hemolytic, hepatic, inflammatory, lipid, and renal parameters. In conclusion, our results highlight the importance of the investigated variants, and their strong association with hydroxyurea efficacy in patients with sickle cell anemia, which may be considered in the future as genetic markers.

CAT -21A>T Variant Alters Hydroxyurea Pharmacokinetic Parameters in Brazilian Children with Sickle Cell Anemia

“…In the present study, we focus on catalase, an endogenous antioxidant enzyme associated with HU conversion. The genotypic and allelic frequencies of the CAT -21A>T variant observed in the present study are consistent with our previous findings [28]. This data also corroborates frequencies previously published [10].…”

“…This hypothesis correlates with lower HU Cmax and higher clearance observed in individuals with the variant genotype when compared to those with the CAT -21AA or AT genotype. Moreover, the reduced levels of the pro-inflammatory biomarker alpha-1 antitrypsin previously reported in CAT -21 TT carriers [28] suggest that higher exposure to the active metabolite may influence HU response. The main limitation of the present study is the low number of individuals included.…”

“…These discrepancies between Brazilian children and other study populations may be due to various factors, including sociodemographic and genetic characteristics, and deserve to be better elucidated. Reports demonstrated the crucial role of polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters in therapeutic response [27,28]. In the present study, we focus on catalase, an endogenous antioxidant enzyme associated with HU conversion.…”

Are Genetic Modifiers the Answer to Different Responses to Hydroxyurea Treatment?—A Pharmacogenetic Study in Sickle Cell Anemia Angolan Children

“…We identified a missense variant, rs1058396, considered benign by PolyPhen, that is probably associated with a poorer response to HU treatment in a dominant model. Previous studies identified polymorphisms in this gene to be associated with HU pharmacokinetics and efficacy [12,33,34].…”

Mathematical Modeling of Hydroxyurea Therapy in Individuals with Sickle Cell Disease

“…Single nucleotide polymorphisms (SNPs) in the SAR1A promoter have been associated with variation in the HbF response of HU-treated individuals [ 20 , 21 ]. Other studies indicated the role of polymorphisms in genes regulating HbF production, HU metabolizing enzymes, and erythroid progenitor proliferation in the varying treatment responses of HU [ 22 , 23 , 24 ].…”