BMC Med. 2019 Jan 17;17(1):1. doi: 10.1186/s12916-018-1207-3.
Plasmodium 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 (PC) and pfk13 genotype based on a large set of individual patient records from Asia and Africa.
A 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 PC values and pfk13 genotype were assessed using multivariable regression models with random effects for study site.
Both the pfk13 genotypes and the PC 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 PC compared to the PC of wild type isolates (all p ≤ 0.002). 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 PC. None of the isolates from four countries in Africa showed a significant difference between the PC 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.
Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.
在大湄公河次区域，青蒿素类药物治疗后疟原虫清除缓慢的感染较为普遍。现已发现一种与清除缓慢表型相关的分子标志物：kelch13 蛋白（pfk13；pf3d7_1343700）螺旋桨区域的单一遗传变化。全球搜索已发现近 200 种不同的非同义突变 pfk13 基因型。大多数突变的发生率较低，且功能意义不确定。为了描述不同 pfk13 突变对寄生虫清除的影响，我们对来自亚洲和非洲的大量个体患者记录进行了基于个体患者数据的荟萃分析，以寄生虫清除半衰期（pc）与 pfk13 基因型之间的关联为基础。
按照 PRISMA 方案进行系统文献综述，以确定 2000 年至 2017 年期间发表的包括频繁寄生虫计数和 pfk13 基因分型的研究。检索了四个数据库（Ovid Medline、PubMed、Ovid Embase 和 Web of Science 核心合集）。符合纳入标准的 18 项研究（15 项来自亚洲，2 项来自非洲，1 项多中心研究，其研究地点分布在两个大陆）被共享。使用具有研究地点随机效应的多变量回归模型评估 log 转换后的 pc 值与 pfk13 基因型之间的关联。
在 3250 名（95%）患者（来自亚洲的 3012 名（93%），来自非洲的 238 名（7%））中，pfk13 基因型和 pc 均可用。在亚洲分离株中，与野生型分离株相比，在五个或更多特定分离株中观察到的所有 pfk13 螺旋桨区域突变等位基因与几何平均 pc 延长 1.5-2.7 倍相关（均 p≤0.002）。此外，位于 pfk13 的恶性疟原虫区域的突变等位基因 E252Q 与 pc 延长 1.5 倍（95%CI 1.4-1.6）相关。来自非洲四个国家的分离株均未显示寄生虫清除时间与 pfk13 螺旋桨区域突变之间存在显著差异。先前已证实六种 pfk13 螺旋桨突变等位基因与寄生虫清除延迟有关。本分析表明，在东南亚，20 个 pfk13 螺旋桨区域突变等位基因与缓慢清除表型密切相关，其中包括 15 个以前未确认的突变。
汇总分析将 20 个 pfk13 螺旋桨区域突变等位基因与清除缓慢表型相关联，包括 15 个以前未确认的突变。
