Genetic architecture of artemisinin-resistant Plasmodium falciparum

被引：406

作者：

Miotto, Olivo ^{[1
,2
,3
]}

Amato, Roberto ^{[1
,2
,4
]}

Ashley, Elizabeth A. ^{[3
,5
]}

MacInnis, Bronwyn ^{[1
,2
]}

Almagro-Garcia, Jacob ^{[1
,2
,4
]}

Amaratunga, Chanaki ^{[6
]}

Lim, Pharath ^{[6
,7
]}

Mead, Daniel ^{[1
]}

Oyolal, Samuel O. ^{[1
]}

Dhorda, Mehul ^{[5
,8
,9
]}

Imwong, Mallika ^{[10
]}

Woodrow, Charles ^{[3
,5
]}

Manske, Magnus ^{[1
,2
]}

Stalker, Jim ^{[1
,2
]}

Drury, Eleanor ^{[1
]}

Campino, Susana ^{[1
,2
]}

Amenga-Etego, Lucas ^{[2
,11
]}

Thuy-Nhien Nguyen Thanh ^{[12
]}

Hien Tinh Tran ^{[5
,12
]}

Ringwald, Pascal ^{[13
]}

Bethellm, Delia ^{[14
]}

Nosten, Francois ^{[3
,5
,15
]}

Phyo, Aung Pyae ^{[3
,5
,15
]}

Pukrittayakamee, Sasithon ^{[10
]}

Chotivanich, Kesinee ^{[10
]}

Chuor, Char Meng ^{[7
]}

Nguon, Chea ^{[7
]}

Suon, Seila ^{[7
]}

Sreng, Sokunthea ^{[7
]}

Newton, Paul N. ^{[5
,16
]}

Mayxay, Mayfong ^{[5
,16
,17
]}

Khanthavong, Maniphone ^{[18
]}

Hongvanthong, Bouasy ^{[18
]}

Htut, Ye ^{[19
]}

Han, Kay Thwe ^{[19
]}

Kyaw, Myat Phone ^{[19
]}

Faiz, Md Abul ^{[20
]}

Fanello, Caterina I. ^{[3
,5
]}

Onyamboko, Marie ^{[5
,21
]}

Mokuolu, Olugbenga A. ^{[22
]}

Jacob, Christopher G. ^{[8
]}

Takala-Harrison, Shannon ^{[8
]}

Plowe, Christopher V. ^{[8
,23
]}

Day, Nicholas P. ^{[3
,5
]}

Dondorp, Arjen M. ^{[3
,5
]}

Spencer, Chris C. A. ^{[2
,4
]}

McVean, Gilean ^{[2
,4
,24
]}

Fairhurst, Rick M. ^{[6
]}

White, Nicholas J. ^{[3
,5
]}

Kwiatkowski, Dominic P. ^{[1
,2
,4
]}

机构：

[1] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[2] Univ Oxford, Ctr Genom & Global Hlth, MRC, Oxford, England

[3] Mahidol Univ, Fac Trop Med, Matlidol Oxtord Trop Med Res Unit, Bangkok 10700, Thailand

[4] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[5] Univ Oxford, Ctr Trop Med, Nuffield Dept Med, Oxford, England

[6] NIAID, Lab Malaria & Vector Res, US NIH, Bethesda, MD 20892 USA

[7] Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia

[8] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA

[9] Mahidol Univ, Asia Reg Ctr, WWARN, Bangkok 10700, Thailand

[10] Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand

[11] Navrongo Hlth Res Ctr, Navrongo, Ghana

[12] Univ Oxford, Clin Res Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam

[13] WHO, Global Malaria Programme, CH-1211 Geneva, Switzerland

[14] USAMC AFRIMS, Dept Immunol & Med, Bangkok, Thailand

[15] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand

[16] Mahosot Hosp, Lao Oxford Mahosot Wellcome Trust Res Unit LOMWRU, Viangchan, Laos

[17] Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos

[18] Minist Hlth, Ctr Mahariol Parasitol & Entomol, Viangchan, Laos

[19] Dept Med Res, Yarigon, Myanmar

[20] Malaria Res Grp & Dev Care Fdn, Dhaka, Bangladesh

[21] Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO

[22] Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria

[23] Univ Maryland, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21201 USA

[24] Univ Oxford, Dept Stat, Oxford, England

来源：

NATURE GENETICS | 2015年 / 47卷 / 03期

基金：

英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

CHLOROQUINE RESISTANCE; PARASITE CLEARANCE; PFMDR2; GENE; MALARIA; SPREAD; EPIDEMIOLOGY; MUTATIONS; PROVINCE; WORLD;

D O I：

10.1038/ng.3189

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.

引用

页码：226 / +

页数：12

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