Sepúlveda Nuno, Grignard Lynn, Curry Jonathan, Mahey Laleta, Bastiaens Guido J H, Tiono Alfred B, Okebe Joseph, Coulibaly Sam A, Gonçalves Bronner P, Affara Muna, Ouédraogo Alphonse, Bougouma Edith C, Sanou Guillaume S, Nébié Issa, Lanke Kjerstin, Sirima Sodiomon B, Dicko Alassane, d'Alessandro Umberto, Clark Taane G, Campino Susana, Chen Ingrid, Eziefula Alice C, Gosling Roly, Bousema Teun, Drakeley Chris
Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
CEAUL - Centro de Estatística e Aplicações da Universidade de Lisboa, Lisbon, Portugal.
Front Genet. 2021 Apr 9;12:645688. doi: 10.3389/fgene.2021.645688. eCollection 2021.
Primaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in individuals suffering from Glucose-6-phospate dehydrogenase (G6PD) deficiency, a genetic condition determined by polymorphisms on the X-linked gene. Most studies on G6PD deficiency and PQ-associated hemolysis focused on the G6PD A- variant, a combination of the two single nucleotide changes G202A (rs1050828) and A376G (rs1050829), although other polymorphisms may play a role. In this study, we tested the association of 20 G6PD single nucleotide polymorphisms (SNPs) with hemolysis measured seven days after low single dose of PQ given at the dose of 0.1 mg/kg to 0.75 mg/kg in 957 individuals from 6 previously published clinical trials investigating the safety and efficacy of this drug spanning five African countries. After adjusting for inter-study effects, age, gender, baseline hemoglobin level, PQ dose, and parasitemia at screening, our analysis showed putative association signals from the common G6PD mutation, A376G [-log(-value) = 2.44] and two less-known SNPs, rs2230037 [-log(-value] = 2.60), and rs28470352 [-log(-value) = 2.15]; A376G and rs2230037 were in very strong linkage disequilibrium with each other ( = 0.978). However, when the effects of these SNPs were included in the same regression model, the subsequent associations were in the borderline of statistical significance. In conclusion, whilst a role for the A- variant is well established, we did not observe an important additional role for other G6PD polymorphisms in determining post-treatment hemolysis in individuals treated with low single-dose PQ.
伯氨喹（PQ）是一种抗疟药物，因其能够清除人类宿主中的成熟配子体，故而具有降低疟疾传播的潜力。然而，由于葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症患者存在药物诱导溶血的额外风险，所以大规模推广使用PQ必须权衡利弊。G6PD缺乏症是一种由X连锁基因多态性决定的遗传疾病。大多数关于G6PD缺乏症和PQ相关溶血的研究都集中在G6PD A-变异体上，它是两个单核苷酸变化G202A（rs1050828）和A376G（rs1050829）的组合，不过其他多态性可能也起作用。在本研究中，我们测试了20个G6PD单核苷酸多态性（SNP）与溶血之间的关联。这20个SNP来自之前发表的6项临床试验中的957名个体，这些试验在五个非洲国家开展，旨在研究该药物的安全性和有效性，研究中给予个体低单剂量的PQ，剂量为0.1mg/kg至0.75mg/kg，在给药七天后测量溶血情况。在对研究间效应、年龄、性别、基线血红蛋白水平、PQ剂量和筛查时的寄生虫血症进行校正后，我们的分析显示，常见的G6PD突变A376G [-log（P值）= 2.44]以及两个鲜为人知的SNP，rs2230037 [-log（P值）= 2.60]和rs28470352 [-log（P值）= 2.15]存在假定的关联信号；A376G和rs2230037彼此处于非常强的连锁不平衡状态（r² = 0.978）。然而，当将这些SNP的效应纳入同一回归模型时，随后的关联处于统计学意义的临界值。总之，虽然A-变异体的作用已得到充分证实，但我们并未观察到其他G6PD多态性在确定低单剂量PQ治疗个体的治疗后溶血方面发挥重要的额外作用。
