喀麦隆5岁以下儿童中宿主候选基因多态性与恶性疟原虫阿莫地喹清除及Fansidar耐药突变体的相关性
Host candidate gene polymorphisms and associated clearance of P. falciparum amodiaquine and fansidar resistance mutants in children less than 5 years in Cameroon.
作者信息
Ali Innocent Mbulli, Evehe Marie-Solange Bebandue, Netongo Palmer Masumbe, Atogho-Tiedeu Barbara, Akindeh-Nji Mbuh, Ngora Honore, Domkam Irenee Kamogne, Diakite Mahamadou, Baldip Khan, Ranford-Cartwright Lisa, Mimche Patrice Nsangou, Lamb Tracey, Mbacham Wilfred Fon
出版信息
Pathog Glob Health. 2014 Oct;108(7):323-33. doi: 10.1179/2047773214Y.0000000159. Epub 2014 Nov 12.
BACKGROUND
In this post-hoc analysis, we determined the influence of single nucleotide polymorphisms in host candidate immune genes on the outcome of drug resistant malaria in Cameroon.
METHODS
Human DNA from 760 patients from a previous clinical trial was subjected to mass spectrometry-based single nucleotide polymorphism (SNP) genotyping. Allele frequencies of candidate immune genes were calculated for 62 SNPs on 17 human chromosomes for their possible involvement in clearance of drug-resistant parasites with the triple mutations of pfcrt76T, pfmdr86Y, and pfmdr1246Y (TY) and pfdhfr51I, pfdhfr59R, pfdhfr108N, and pfdhps437G (IRNG) which were determined by dotblot or PCR-restriction analysis. Differences in SNP frequencies and association analysis were carried out by comparing Chi-square odds ratios (ORs) and stratified by Mantel-Haenzel statistics. An adjusted P value (OR) <0·0008 was considered significant.
RESULTS
Post-treatment drug failure rates were amodiaquine (36·4%); sulpadoxine/pyrimethamine-amodiaquine combination (15·4%); and sulphadoxine/pyrimethamine (18·1%). SNPs in IL22, IL-4R1, and CD36 appeared to have been associated with clearance of resistant parasites [p = 0·017, OR (C allele):1·44, 95% CI (OR): 1·06-1·95]; [P = 0·014, OR = 1·31, 95% CI (OR): 1·07-1·83]; [P = 5·78×10(-5), OR = 0·27, 95%CI (OR): 0·13-0·54], respectively, with high fever (>39°C for 48 hours) [IL-22, P = 0·01, OR = 1·5, 95% CI (OR): 1·8-2·1] and also in high frequency among the Fulani participants [P = 0·006, OR = 1·83, 95% CI (OR): 1·11-3·08)]. The CD36-1264 null allele was completely absent in the northern population.
CONCLUSION
Independent association of SNPs in IL22 and IL-4 with clearance of amodiaquine- and sulphadoxine/pyrimethamine-resistant parasites did not reach statistical significance, but may suggest that not all drug-resistant mutants are adversely affected by the same immune-mediated mechanisms of clearance.
背景
在这项事后分析中，我们确定了宿主候选免疫基因中的单核苷酸多态性对喀麦隆耐药疟疾治疗结果的影响。
方法
对先前一项临床试验中760名患者的人类DNA进行基于质谱的单核苷酸多态性（SNP）基因分型。计算了17条人类染色体上62个SNP的候选免疫基因的等位基因频率，以确定它们可能参与清除具有pfcrt76T、pfmdr86Y和pfmdr1246Y三重突变（TY）以及pfdhfr51I、pfdhfr59R、pfdhfr108N和pfdhps437G（IRNG）的耐药寄生虫，这些突变通过斑点印迹或PCR限制性分析确定。通过比较卡方优势比（OR）进行SNP频率差异和关联分析，并按Mantel-Haenzel统计分层。调整后的P值（OR）<0·0008被认为具有显著性。
结果
治疗后药物失败率分别为：阿莫地喹（36·4%）；磺胺多辛/乙胺嘧啶-阿莫地喹联合用药（15·4%）；以及磺胺多辛/乙胺嘧啶（18·1%）。IL22、IL-4R1和CD36中的SNP似乎与耐药寄生虫的清除有关[p = 0·017，OR（C等位基因）：1·44，95%CI（OR）：1·06 - 1·95]；[P = 0·014，OR = 1·31，95%CI（OR）：1·07 - 1·83]；[P = 5·78×10(-5)，OR = 0·27，95%CI（OR）：0·13 - 0·54]，分别与高热（>39°C持续48小时）[IL-22，P = 0·01，OR = 1·5，95%CI（OR）：1·8 - 2·1]有关，并且在富拉尼参与者中频率也较高[P = 0·006，OR = 1·83，95%CI（OR）：1·11 - 3·08]。CD36 - 1264无效等位基因在北方人群中完全不存在。
结论
IL22和IL-4中的SNP与阿莫地喹和磺胺多辛/乙胺嘧啶耐药寄生虫清除的独立关联未达到统计学显著性，但可能表明并非所有耐药突变体都受到相同免疫介导清除机制的不利影响。
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