pfmdr1 基因而非 pfnhe-1 基因的多态性与泰国恶性疟原虫分离株体外奎宁敏感性相关。
Polymorphisms of the pfmdr1 but not the pfnhe-1 gene is associated with in vitro quinine sensitivity in Thai isolates of Plasmodium falciparum.
机构信息
Department of Parasitology, Phramongkutklao College of Medicine, 315 Ratchawithi Rd., Ratchathewi, Bangkok, Thailand.
出版信息
Malar J. 2012 Jan 5;11:7. doi: 10.1186/1475-2875-11-7.
BACKGROUND
The emergence of Plasmodium falciparum resistance to most currently used anti-malarial drugs is a major problem in malaria control along the Thai-Myanmar and Thai-Cambodia borders. Quinine (QN) with tetracycline/doxycycline has been used as the second-line treatment for uncomplicated falciparum malaria. In addition, QN monotherapy has been the first-line treatment for falciparum malaria in pregnant women. However, reduced in vitro and in vivo responses to QN have been reported. To date, a few genetic markers for QN resistance have been proposed including Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1), and P. falciparum Na+/H+ exchanger (pfnhe-1). This study was to investigate the role of the pfmdr1 and pfnhe-1 gene on in vitro QN sensitivity in Thai isolates of P. falciparum.
METHODS
Eighty-five Thai isolates of P. falciparum from the Thai-Myanmar and Thai-Cambodia borders from 2003-2008 were determined for in vitro QN sensitivity using radioisotopic assay. Polymorphisms of the pfmdr1 and pfnhe-1 gene were determined by PCR-RFLP and sequence analysis. Associations between the in vitro QN sensitivity and the polymorphisms of the pfmdr1 and pfnhe-1 gene were evaluated.
RESULTS
The mean QN IC50 was 202.8 nM (range 25.7-654.4 nM). Only four isolates were QN resistant when the IC50 of >500 nM was used as the cut-off point. Significant associations were found between the pfmdr1 mutations at codons N86Y and N1042D and in vitro QN sensitivity. However, no associations with the number of DNNND, DDNNNDNHNDD, and NHNDNHNNDDD repeats in the microsatellite ms4760 of the pfnhe-1 gene were identified.
CONCLUSION
Data from the present study put doubt regarding the pfnhe-1 gene as to whether it could be used as the suitable marker for QN resistance in Thailand. In contrast, it confirms the influence of the pfmdr1 gene on in vitro QN sensitivity.
背景
恶性疟原虫对目前大多数抗疟药物的耐药性的出现是泰缅和泰柬边境疟疾控制的一个主要问题。奎宁（QN）联合四环素/强力霉素已被用作无并发症恶性疟的二线治疗药物。此外，QN 单药治疗已成为孕妇恶性疟的一线治疗药物。然而，已经报道了对 QN 的体外和体内反应降低。迄今为止，已经提出了一些 QN 耐药的遗传标记，包括恶性疟原虫氯喹耐药转运蛋白（pfcrt）、恶性疟原虫多药耐药 1（pfmdr1）和恶性疟原虫 Na+/H+交换蛋白（pfnhe-1）。本研究旨在探讨 pfmdr1 和 pfnhe-1 基因在泰国恶性疟原虫分离株体外 QN 敏感性中的作用。
方法
从 2003 年至 2008 年，从泰缅和泰柬边境采集了 85 株来自泰国的恶性疟原虫分离株，采用放射性同位素测定法测定体外 QN 敏感性。采用 PCR-RFLP 和序列分析方法检测 pfmdr1 和 pfnhe-1 基因的多态性。评估体外 QN 敏感性与 pfmdr1 和 pfnhe-1 基因多态性之间的关系。
结果
QN 的平均 IC50 为 202.8 nM（范围 25.7-654.4 nM）。当 IC50 ＞500 nM 作为临界点时，只有 4 株分离株为 QN 耐药。pfmdr1 密码子 N86Y 和 N1042D 的突变与体外 QN 敏感性之间存在显著相关性。然而，pfnhe-1 基因微卫星 ms4760 中的 DNNND、DDNNDNHNDD 和 NHNDNHNNDDD 重复数与体外 QN 敏感性无相关性。
结论
本研究的数据对 pfnhe-1 基因是否可以作为泰国 QN 耐药的合适标记提出了质疑。相反，它证实了 pfmdr1 基因对体外 QN 敏感性的影响。
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