一項研究發(fā)現(xiàn)了與青蒿素耐藥性有關(guān)的4個惡性瘧原蟲的遺傳位點,。大多數(shù)瘧疾流行的國家在聯(lián)合療法中使用青蒿素作為治療惡性瘧原蟲的一線療法。Christopher V. Plowe及其同事對從最近出現(xiàn)了對青蒿素耐藥的惡性瘧原蟲的柬埔寨西部,、孟加拉國和泰國進行的青蒿素療法有效性臨床試驗中收集的惡性瘧原蟲DNA的8079個單核苷酸多態(tài)（SNPs）——這是一種遺傳變異的形式——進行了遺傳分型,。這組作者報告說，與來自孟加拉國的病人相比,，來自柬埔寨西部的大多數(shù)接受青蒿素治療的病人的瘧原蟲清除被嚴(yán)重延遲了,，而泰國的病人表現(xiàn)出了一種混合的響應(yīng),。這組作者發(fā)現(xiàn)4個單核苷酸多態(tài)（SNPs）——有兩個分別在10號和14號染色體，另外兩個在13號染色體上——與瘧原蟲清除的延遲有顯著聯(lián)系,。在10號和13號染色體上的這些單核苷酸多態(tài)（SNPs）位于或者靠近參與一個DNA損傷耐受路徑的基因,，這種路徑可能因為抗瘧藥物治療而被激活。這組作者說,，在10號染色體上的一個單核苷酸多態(tài)（SNPs）和在13號染色體上的一個單核苷酸多態(tài)（SNPs）可能作為瘧原蟲清除延遲的分子標(biāo)記,，而且可能用于監(jiān)測東南亞的青蒿素耐藥性。(生物谷Bioon.com)
doi: 10.1073/pnas.1211205110
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Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia
, Olivo Miottod,e,2, Arjen M. Dondorpe, Mark M. Fukudaf, Francois Nostene,g, Harald Noedlh, Mallika Imwongi, Delia Bethellf, Youry Sej, Chanthap Lonj, Stuart D. Tynerf, David L. Saundersf, Duong Socheatk, Frederic Arieyl, Aung Pyae Phyoe,g, Peter Starzengruberh, Hans-Peter Fuehrerh, Paul Swobodah, Kasia Stepniewskam, Jennifer Fleggm, Cesar Arzen, Gustavo C. Cerqueiran, Joana C. Silvan, Stacy M. Ricklefso, Stephen F. Porcellao, Robert M. Stephensp, Matthew Adamsa, Leo J. Kenefica, Susana Campinod,q, Sarah Auburnq, Bronwyn MacInnisd,q, Dominic P. Kwiatkowskid,q, Xin-zhuan Sur, Nicholas J. Whitee, Pascal Ringwalds, and Christopher V. Plowea,3
The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.
