Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatmentsa WWARN individual patient data meta-analysis
Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatmentsa WWARN individual patient data meta-analysis
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DOI：
10.1186/s12916-018-1207-3
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发表时间：
2019-01-17
期刊：
影响因子：
9.3
通讯作者：
Woodrow, Charles
中科院分区：
文献类型：
--
作者：
Amaratunga, Chanaki;Andrianaranjaka, Voahangy Hanitriniaina;Woodrow, Charles
背景以青蒿素为基础的治疗后，恶性疟原虫清除缓慢的感染在大湄公河次区域广泛存在。已经确定了一个慢清除表型的分子标记：kelch13蛋白螺旋桨区域内的单一基因变化(pfk13；pf3D7_1343700)。全球搜索已经确定了近200种不同的非同义突变pfk13基因类型。大多数突变发生在低发病率，并具有不确定的功能意义。为了表征不同的pfk13突变对寄生虫清除的影响，我们基于来自亚洲和非洲的大量个人患者记录，对寄生虫清除半衰期(PC1/2)和pfk13基因之间的关系进行了个体患者数据荟萃分析。方法遵循Prisma方案进行系统的文献综述，以确定2000年至2017年发表的研究，包括寄生虫频繁计数和pfk13基因分型。检索四个数据库(Ovid Medline、PubMed、Ovid Embase和Web of Science Core Collection)。18项研究(15项来自亚洲，2项来自非洲，1项多中心研究，地点分布在两个大陆)符合纳入标准并被分享。结果3250例(95%)患者中存在pfk13基因和pfk13基因，其中3012例来自亚洲(93%)，238例来自非洲(7%)。在亚洲分离株中，在5个或更多特定分离株中观察到的所有pfk13螺旋桨区突变等位基因与野生分离株的PC1/2相比，几何平均值PC1/2长1.5-2.7倍(均为p0.002)。此外，位于恶性疟原虫pfk13区的突变等位基因E252Q与PC1/2延长1.5倍(95%可信区间1.4-1.6)有关。来自非洲4个国家的分离株与存在或不存在pfk13螺旋区突变的寄生虫的PC1/2没有显著差异。这一分析表明，另外15个pfk13等位基因与东南亚地区的慢清除表型密切相关。结论综合分析将20个pfk13螺旋桨区域突变等位基因与慢清除表型相关联，其中包括15个以前未证实的突变。
BackgroundPlasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa.MethodsA systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site.ResultsBoth the pfk13 genotypes and the PC1/2 were available from 3250 (95%) patients (n=3012 from Asia (93%), n=238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC1/2 compared to the PC1/2 of wild type isolates (all p0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC1/2. None of the isolates from four countries in Africa showed a significant difference between the PC1/2 of parasites with or without pfk13 propeller region mutations.Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.ConclusionPooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.