In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria.
In vitro amodiaquine resistance and its association with mutations in pfcrt and pfmdr1 genes of Plasmodium falciparum isolates from Nigeria.
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DOI：
10.1016/j.actatropica.2011.08.013
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发表时间：
2011-12
期刊：
影响因子：
2.7
通讯作者：
Happi, C. T.
中科院分区：
文献类型：
--
作者：
Folarin, O. A.;Bustamante, C.;Gbotosho, G. O.;Sowunmi, A.;Zalis, M. G.;Oduola, A. M. J.;Happi, C. T.
目前，阿莫地喹 (AQ) 在非洲大多数流行国家被用作与青蒿琥酯联合治疗单纯性疟疾的伙伴药物。在缺乏青蒿素抗性分子标记的情况下，AQ 抗性分子标记可能有助于监测寄生虫对青蒿素-阿莫地喹组合抗性的发展和传播。本研究旨在评估 pfcrt 和 pfmdr1 基因多态性以及寄生虫体外敏感性对恶性疟原虫阿莫地喹耐药性流行病学监测的潜在作用。改良的裂殖体抑制试验用于测定 98 名患者的恶性疟原虫分离株对阿莫地喹的体外敏感性。通过巢式 PCR 和测序确定寄生虫 pfcrt 和 pfmdr1 基因的多态性。 97 株恶性疟原虫分离株中 AQ 50% 抑制浓度 (IC-50) 的几何平均值 (GM) 为 20.48nM (95% CI 16.53–25.36nM)。根据 AQ 体外敏感性的临界值，87% (84) 的恶性疟原虫分离株对 AQ 敏感（GM IC-50= 16.32nM；95%CI 13.3–20.04nM），而 13% 对 AQ 体外耐药（GM IC-50= 88.73nM；95%CI） 69.67–113.0nM）。分子分析显示，突变型 CVIET pfcrt 单倍型、突变型 pfmdr1Tyr86 等位基因和双突变型 CVIET pfcrt 单倍型+pfmdr1Tyr86 的存在率分别为 72%、49% 和 35%。含有野生型 pfcrt CVMNK 单倍型 + pfmdr1Asn86 等位基因的分离株的 GM IC-50 (3.93nM; 95%CI 1.82–8.46) 显着低于含有双突变 pfcrtCVIET 单倍型 + pfmdr1Tyr86 等位基因的分离株 (p=0.001) （50.40nM；95%CI 40.17–63.24）。这项研究的结果表明，pfcrt 和 pfmdr1 基因的多态性对于 AQ 抗性很重要，因此可能有助于恶性疟原虫对 AQ 抗性的流行病学监测。
Amodiaquine (AQ) is currently being used as a partner drug in combination with artesunate for treatment of uncomplicated malaria in most endemic countries of Africa. In the absence of molecular markers of artemisinin resistance, molecular markers of resistance to AQ may be useful for monitoring the development and spread of parasites resistance to Artesunate-Amodiaquine combination. This study was designed to assess the potential role of polymorphisms on pfcrt and pfmdr1 genes and parasite in vitro susceptibility for epidemiological surveillance of amodiaquine resistance in Plasmodium falciparum. The modified schizont inhibition assay was used to determine in vitro susceptibility profiles of 98 patients' isolates of Plasmodium falciparum to amodiaquine. Polymorphisms on parasites pfcrt and pfmdr1 genes were determined with nested PCR followed by sequencing. The geometric mean (GM) of AQ 50% inhibitory concentration (IC-50) in the 97 P. falciparum isolates was 20.48nM (95% CI 16.53–25.36nM). Based on the cut-off value for AQ in vitro susceptibility, 87% (84) of the P. falciparum isolates were sensitive to AQ (GM IC-50= 16.32nM; 95%CI 13.3–20.04nM) while 13% were resistant to AQ in vitro (GM IC-50= 88.73nM; 95%CI 69.67–113.0nM). Molecular analysis showed presence of mutant CVIET pfcrt haplotype, mutant pfmdr1Tyr86 allele and the double mutant CVIET pfcrt haplotype+pfmdr1Tyr86 in 72%, 49% and 35% respectively. The GM IC-50 of isolates harboring the wild-type pfcrt CVMNK haplotype+ pfmdr1Asn86 allele (3.93nM; 95%CI 1.82–8.46) was significantly lower (p=0.001) than those isolates harboring the double mutant pfcrtCVIET haplotype+pfmdr1Tyr86 allele (50.40nM; 95%CI 40.17–63.24). Results from this study suggest that polymorphisms in pfcrt and pfmdr1 genes are important for AQ resistance and therefore may be useful for epidemiological surveillance of P. falciparum resistance to AQ.
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影响因子：
16
作者：
Johnson, DJ;Fidock, DA;Ward, SA
通讯作者：
Ward, SA
影响因子：
4.9
作者：
Humphreys, G. S.;Merinopoulos, I.;Hallett, R. L.
通讯作者：
Hallett, R. L.
影响因子：
3.2
作者：
Holmgren, Gabrielle;Hamrin, Johan;Bjorkman, Anders
通讯作者：
Bjorkman, Anders
影响因子：
--
作者：
Maguire, JD;Susanti, AI;Baird, JK
通讯作者：
Baird, JK
影响因子：
6.4
作者：
Djimdé, AA;Dolo, A;Doumbo, OK
通讯作者：
Doumbo, OK