PDF(Pubmed)
Abstract：
Sickle cell anemia (SCA) is an inherited disease affecting the hemoglobin that is particularly common in sub-Saharan Africa. Although monogenic, phenotypes are markedly heterogeneous in terms of severity and life span. Hydroxyurea is still the most common treatment for these patients, and the response to treatment is highly variable and seems to be an inherited trait. Therefore, identifying the variants that might predict hydroxyurea response is important for identifying patients who will have a poorer or non-response to treatment, and the ones that are more prone to suffer from severe side effects. In the present pharmacogenetic study, we analyzed the exons of 77 genes described in the literature as potentially associated with hydroxyurea metabolism in Angolan children treated with hydroxyurea and evaluated the drug response considering fetal hemoglobin levels, other hematological and biochemical parameters, hemolysis, number of vaso-occlusive crises and hospitalizations. Thirty variants were identified in 18 of those genes as possibly associated with drug response, five of them in gene DCHS2. Other polymorphisms in this gene were also associated with hematological, biochemical and clinical parameters. Further research examining the maximum tolerated dose and fixed dose with a larger sample size is necessary to corroborate these findings.
摘要：
镰状细胞性贫血（SCA）是一种影响血红蛋白的遗传性疾病，在撒哈拉以南非洲尤其常见。虽然是单基因的，表型在严重程度和寿命方面具有明显的异质性。羟基脲仍然是这些患者最常见的治疗方法，对治疗的反应是高度可变的，似乎是一种遗传特征。因此,识别可能预测羟基脲反应的变体对于识别对治疗反应较差或无反应的患者很重要，和那些更容易遭受严重副作用的人。在目前的药物遗传学研究中，在接受羟基脲治疗的安哥拉儿童中，我们分析了文献中描述的与羟基脲代谢潜在相关的77个基因的外显子，并评估了考虑胎儿血红蛋白水平的药物反应，其他血液和生化参数，溶血,血管闭塞危象和住院次数。在其中18个基因中鉴定出30种变异可能与药物反应有关，其中五个在基因DCHS2中。该基因的其他多态性也与血液学，生化和临床参数。需要进一步研究以更大的样本量检查最大耐受剂量和固定剂量以证实这些发现。
