Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?
Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?
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DOI：
10.1128/aac.49.6.2180-2188.2005
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发表时间：
2005-06-01
影响因子：
4.9
通讯作者：
Nosten, F
中科院分区：
文献类型：
--
作者：
Anderson, TJC;Nair, S;Nosten, F
Mu等人。(Mu J.，M.T.Ferdig，X.冯，D.A.喜悦，J.Duan，T.Furuya，G.Subramanian，L.Aravind，R.A.Cooper，J.C.Wootton，M.Xong，和X.Z.Su，Mol.微生物。49：977-989,2003)最近报道了9个新的候选转运蛋白基因与体外对氯喹(CQ)和奎宁(QN)的耐药性之间的令人兴奋的关联，其中6个座位在东南亚人群样本中显示与CQ或QN相关。我们通过检测这些基因的多态和从泰国-缅甸边境收集的寄生虫对8种药物的体外耐药性来复制和扩展这项工作。为了最大限度地减少多次检测的问题，我们使用了两阶段研究设计，同时为了最大限度地减少种群结构造成的问题，我们分析了从单一诊所收集的寄生虫分离株。我们首先研究了108个独特的单克隆寄生虫分离株的基因型别和药物反应之间的关系。我们发现pfmdr的单核苷酸多态与甲氟喹(MFQ)、青蒿琥酯(AS)和鲁米芬(Lum)的反应有很强的相关性。我们还观察到一个ABC转运体(G7)与对QN和AS的反应以及另一个ABC转运体(G49)与对双氢青蒿素(DRA)的反应之间的关联。我们重新检查了来自同一地点的199个独特的单克隆感染的独立样本中的显著相关性。在第一次调查中发现的与pfmdr-1042的显著关联仍然存在。然而，除了G7-青蒿琥酯的关联外，观察到的与9个新的候选转运蛋白的所有其他关联都消失了。我们还检查了标记之间的连锁不平衡(LD)和药物反应之间的表型相关性。我们发现了基因之间最小的LD。此外，我们没有发现氯喹和奎宁反应之间的相关性，尽管我们确实发现MFQ、QN、AS、DRA和Lum之间存在预期的强相关性。总而言之，我们没有发现8/9候选基因与8种不同抗疟疾药物疗效之间存在关联的证据。然而，在G7中观察到的3-碱基插入序列与AS反应之间的一致关联值得进一步研究。
Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DRA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr- 1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DRA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and response to eight different antimalarial drugs. However, the consistent association observed between a 3-bp indel in G7 and AS response merits further investigation.