Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, QLD, Australia.
School of Public Health and Social Work, Queensland University of Technology, Brisbane, QLD, Australia.
Malar J. 2019 Apr 18;18(1):140. doi: 10.1186/s12936-019-2774-2.
Primaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated.
Genomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999-2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3-5 (n = 9) relapses within the ADF-R group.
16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group.
CYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.
伯氨喹啉是一种具有抗疟原虫休眠体活性的 8-氨基喹啉，它在人体内通过细胞色素 P450 2D6（CYP2D6）代谢为其活性代谢物。人类 CYP2D6 的活性可能会影响伯氨喹啉的代谢和接受伯氨喹啉抗复燃治疗（PART）后发生疟原虫复燃的风险。在这项研究中， retrospectively 调查了澳大利亚国防军（ADF）人员的 CYP2D6 谱及其与 PART 结果的关系。
从部署到巴布亚新几内亚（1999 年）和东帝汶（1999-2000 年）执行维和任务并在返回澳大利亚后经历复发的 ADF 人员储存和识别血清或血液样本中分离基因组 DNA，他们在返回澳大利亚之前接受了 PART。通过 PCR 和 Sanger 测序确定 CYP2D6 等位基因类型。比较未经历间日疟原虫（ADF-NR，n=48）和至少经历一次（ADF-R，n=109）复发的人员以及 ADF-R 组中经历 1（n=79）、2（n=21）和 3-5（n=9）次复发的人员之间的 CYP2D6 等位基因频率、预测表型和活性评分。
在 157 名 ADF 人员中观察到 16 个 CYP2D6 等位基因。等位基因 *1、*4、*2 和 *41 是主要等位基因（>5%）。ADF-NR 组的 CYP2D6 等位基因频率谱与欧洲人群相匹配。与欧洲人群和 ADF-NR 组相比，ADF-R 组中非功能性 CYP2D6 等位基因的比例增加。然而，ADF-R 组和 ADF-NR 组之间以及 ADF-R 组中经历多次复发的亚组之间，CYP2D6 预测表型和活性评分的频率没有差异。
基于等位基因分类的 CYP2D6 表型或活性评分不是该 ADF 队列中发生间日疟原虫复发的主要因素。其他因素，如对伯氨喹啉的依从性和/或寄生虫耐受性，可能是该队列中发生间日疟原虫复发的原因。
