CYP2D6 Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar.
CYP2D6 Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar.
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DOI：
10.3389/fphar.2021.654054
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发表时间：
2021
影响因子：
5.6
通讯作者：
Zimmerman PA
中科院分区：
文献类型：
--
作者：
Mehlotra RK;Gaedigk A;Howes RE;Rakotomanga TA;Ratsimbasoa AC;Zimmerman PA
间日疟原虫是五种人类疟疾寄生虫之一，具有广泛的地理分布，可引起严重的疾病和致命的后果。它有能力从休眠的肝脏阶段（催眠虫）复发，在急性血液阶段感染清除后数周至数月。8-氨基喹啉类药物伯氨喹（PQ）可以清除催眠虫，因此可以用作抗复发治疗剂。最近，多项研究发现，细胞色素P450 2D 6（CYP 2D 6）基因多态性会损害其疗效; CYP 2D 6活性降低或缺失会导致PQ治疗失败。本研究旨在描述CYP 2D 6在马达加斯加的遗传变异，那里的人口来自亚洲和非洲人口之间的混合，间日疟是地方性的，PQ可以很快部署，以实现全国疟疾消除。在两个卫生区的211份样本中，CYP 2D 6 *10、*17、*29、*36+*10和 *41等位基因的频率为3.55- 17.06%。此外，还观察到非功能性等位基因，其中最常见的是CYP 2D 6 *4（2.13%）、*5（1.66%）和 * 4x 2基因重复（1.42%）。考虑到这些频率，预计34.6%的个体为中间代谢型（IM），酶活性评分（AS）≤ 1.0; IM表型和AS ≤ 1.0均与PQ治疗失败相关。此外，等位基因和基因型频率分布增加了马达加斯加人口构成一个独特的，亚洲-非洲混合起源的考古和基因组证据。这项探索性研究的结果提供了有关基因组特征的新见解，这些基因组特征可能影响PQ代谢进入其活性状态，并可能使PQ治疗在人类遗传多样性中得以优化，这对于实现间日疟原虫消除至关重要。
Plasmodium vivax is one of the five human malaria parasite species, which has a wide geographical distribution and can cause severe disease and fatal outcomes. It has the ability to relapse from dormant liver stages (hypnozoites), weeks to months after clearance of the acute blood-stage infection. An 8-aminoquinoline drug primaquine (PQ) can clear the hypnozoites, and thus can be used as an anti-relapse therapeutic agent. Recently, a number of studies have found that its efficacy is compromised by polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene; decreased or absence of CYP2D6 activity contributes to PQ therapeutic failure. The present study sought to characterize CYP2D6 genetic variation in Madagascar, where populations originated from admixture between Asian and African populations, vivax malaria is endemic, and PQ can be deployed soon to achieve national malaria elimination. In a total of 211 samples collected from two health districts, CYP2D6 decreased function alleles CYP2D6*10, *17, *29, *36+*10, and *41 were observed at frequencies of 3.55–17.06%. In addition, nonfunctional alleles were observed, the most common of which were CYP2D6*4 (2.13%), *5 (1.66%), and the *4x2 gene duplication (1.42%). Given these frequencies, 34.6% of the individuals were predicted to be intermediate metabolizers (IM) with an enzyme activity score (AS) ≤ 1.0; both the IM phenotype and AS ≤ 1.0 have been found to be associated with PQ therapeutic failure. Furthermore, the allele and genotype frequency distributions add to the archaeological and genomic evidence of Malagasy populations constituting a unique, Asian-African admixed origin. The results from this exploratory study provide fresh insights about genomic characteristics that could affect the metabolism of PQ into its active state, and may enable optimization of PQ treatment across human genetic diversity, which is critical for achieving P. vivax elimination.
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影响因子：
10.7
作者：
Brucato N;Kusuma P;Cox MP;Pierron D;Purnomo GA;Adelaar A;Kivisild T;Letellier T;Sudoyo H;Ricaut FX
通讯作者：
Ricaut FX
影响因子：
5.7
作者：
Bourgard C;Albrecht L;Kayano ACAV;Sunnerhagen P;Costa FTM
通讯作者：
Costa FTM
影响因子：
5.4
作者：
Adams JH;Mueller I
通讯作者：
Mueller I
影响因子：
1.1
作者：
Dijanic, Christopher;Nickerson, Jillian;Fabbri, Marilyn
通讯作者：
Fabbri, Marilyn
影响因子：
2
作者：
Ariffin, Norliza Mat;Islahudin, Farida;Makmor-Bakry, Mohd
通讯作者：
Makmor-Bakry, Mohd