CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study.
CYP2D6 activity and the risk of recurrence of Plasmodium vivax malaria in the Brazilian Amazon: a prospective cohort study.
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DOI：
10.1186/s12936-017-2139-7
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发表时间：
2018-02-01
期刊：
影响因子：
3
通讯作者：
Suarez-Kurtz G
中科院分区：
文献类型：
--
作者：
Brasil LW;Rodrigues-Soares F;Santoro AB;Almeida ACG;Kühn A;Ramasawmy R;Lacerda MVG;Monteiro WM;Suarez-Kurtz G
CYP 2D 6途径介导伯氨喹在肝细胞中活化为活性代谢物。CYP 2D 6具有高度多态性，编码具有正常、降低、无效或增加活性的CYP 2D 6亚型。假设CYP 2D 6功能缺陷的间日疟原虫疟疾患者伯氨喹预防复发失败的风险增加。本研究的目的是调查CYP 2D 6多态性和推断CYP 2D 6表型与疟疾复发的患者从巴西西部亚马逊，氯喹/伯氨喹联合治疗的关联。前瞻性队列包括间日疟原虫疟疾患者，他们在完成氯喹/伯氨喹治疗后随访6个月。复发被定义为一次或多次疟疾发作，在首次发作后28-180天。在Fast 7500实时分析系统中使用TaqMan检测试剂盒对9种CYP 2D 6 SNP和拷贝数变异进行基因分型。推断CYP 2D 6星星等位基因（单倍型）、双倍型和CYP 2D 6表型，并使用活性评分系统来定义CYP 2D 6双倍型的功能。CYP 2D 6活性评分（AS）在≤ 1（gPM、gIM和gNM-S表型）和≥ 1.5（gNM-F和gUM表型）时进行二分。在190例患者中成功进行了基因分型（44例复发，146例无复发）。CYP 2D 6活性降低表型个体的复发率较高（校正相对风险= 1.89，95% CI 1.01-3.70; p = 0.049）。归因危险度和人群归因分数分别为11.5%和9.9%。AS ≤ 1与≥ 1.5的患者之间从间日疟原虫首次发病至复发的时间无差异（p = 0.917）。结果表明，CYP 2D 6多态性与氯喹伯氨喹联合治疗后间日疟复发风险增加有关。这种相关性被解释为CYP 2D 6酶活性降低的患者中伯氨喹转化为其活性代谢物减少的结果。
CYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy. The prospective cohort consisted of P. vivax malaria patients who were followed for 6 months after completion of the chloroquine/primaquine therapy. Recurrence was defined as one or more malaria episodes, 28–180 days after the initial episode. Genotyping for nine CYP2D6 SNPs and copy number variation was performed using TaqMan assays in a Fast 7500 Real-Time System. CYP2D6 star alleles (haplotypes), diplotypes and CYP2D6 phenotypes were inferred, and the activity score system was used to define the functionality of the CYP2D6 diplotypes. CYP2D6 activity scores (AS) were dichotomized at ≤ 1 (gPM, gIM and gNM-S phenotypes) and ≥ 1.5 (gNM-F and gUM phenotypes). Genotyping was successfully performed in 190 patients (44 with recurrence and 146 without recurrences). Recurrence incidence was higher in individuals presenting reduced activity CYP2D6 phenotypes (adjusted relative risk = 1.89, 95% CI 1.01–3.70; p = 0.049). Attributable risk and population attributable fraction were 11.5 and 9.9%, respectively. The time elapsed from the first P. vivax malaria episode until the recurrence did not differ between patients with AS of ≤ 1 versus ≥ 1.5 (p = 0.917). The results suggest that CYP2D6 polymorphisms are associated with increased risk of recurrence of vivax malaria, following chloroquine–primaquine combined therapy. This association is interpreted as the result of reduced conversion of primaquine into its active metabolites in patients with reduced CYP2D6 enzymatic activity.
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影响因子：
3
作者：
Pybus BS;Marcsisin SR;Jin X;Deye G;Sousa JC;Li Q;Caridha D;Zeng Q;Reichard GA;Ockenhouse C;Bennett J;Walker LA;Ohrt C;Melendez V
通讯作者：
Melendez V
影响因子：
6.7
作者：
Gaedigk, A.;Simon, S. D.;Leeder, J. S.
通讯作者：
Leeder, J. S.
影响因子：
3
作者：
Brasil, Larissa W.;Barbosa, Laila R. A.;Ramasawmy, Rajendranath
通讯作者：
Ramasawmy, Rajendranath
影响因子：
3
作者：
Vitor-Silva, Sheila;Siqueira, Andre Machado;Guimaraes Lacerda, Marcus Vinicius
通讯作者：
Guimaraes Lacerda, Marcus Vinicius
DOI：
10.1093/trstmh/trt015
发表时间：
2013-05-01
影响因子：
2.2
作者：
Santana, Marli S.;Monteiro, Wuelton M.;Alecrim, Maria G.
通讯作者：
Alecrim, Maria G.