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Frontiers of Medicine

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Front. Med.    2022, Vol. 16 Issue (1) : 83-92    https://doi.org/10.1007/s11684-021-0894-x
RESEARCH ARTICLE
Prevalence of antifolate drug resistance markers in Plasmodium vivax in China
Fang Huang1(), Yanwen Cui1, He Yan1, Hui Liu2, Xiangrui Guo3, Guangze Wang4, Shuisen Zhou1, Zhigui Xia1
1. National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, WHO Collaborating Center for Tropical Diseases, National Centre for International Research on Tropical Diseases, NHC Key Laboratory of Parasite and Vector Biology (National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention), Shanghai 200025, China
2. Yunnan Institute of Parasitic Diseases, Puer 665000, China
3. Yingjiang County for Disease Control and Prevention, Yingjiang 679300, China
4. Hainan Center for Disease Control & Prevention, Haikou 570203, China
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Abstract

The dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes of Plasmodium vivax, as antifolate resistance-associated genes were used for drug resistance surveillance. A total of 375 P. vivax isolates collected from different geographical locations in China in 2009–2019 were used to sequence Pvdhfr and Pvdhps. The majority of the isolates harbored a mutant type allele for Pvdhfr (94.5%) and Pvdhps (68.2%). The most predominant point mutations were S117T/N (77.7%) in Pvdhfr and A383G (66.8%) in Pvdhps. Amino acid changes were identified at nine residues in Pvdhfr. A quadruple-mutant haplotype at 57, 58, 61, and 117 was the most frequent (57.4%) among 16 distinct Pvdhfr haplotypes. Mutations in Pvdhps were detected at six codons, and the double-mutant A383G/A553G was the most prevalent (39.3%). Pvdhfr exhibited a higher mutation prevalence and greater diversity than Pvdhps in China. Most isolates from Yunnan carried multiple mutant haplotypes, while the majority of samples from temperate regions and Hainan Island harbored the wild type or single mutant type. This study indicated that the antifolate resistance levels of P. vivax parasites were different across China and molecular markers could be used to rapidly monitor drug resistance. Results provided evidence for updating national drug policy and treatment guidelines.
Keywords drug resistance      antifolates      molecular markers      Plasmodium vivax      China     
Corresponding Author(s): Fang Huang   
Just Accepted Date: 19 January 2022   Online First Date: 03 March 2022    Issue Date: 28 March 2022
 Cite this article:   
Fang Huang,Yanwen Cui,He Yan, et al. Prevalence of antifolate drug resistance markers in Plasmodium vivax in China[J]. Front. Med., 2022, 16(1): 83-92.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0894-x
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I1/83
Locations Sites Pvdhfr
n WT I13L A15V F57L/Ia S58Rb T61M R76G H99S S117T/Nc I173L
Northeastern Dandong 7 1 2 1 2
Central Suining 16 10 6
Southwestern Nyingchi 3 1 2 1
Southern Hainan 3 3 3
Southwestern Yingjiang 58 3 16 28 16 19 28
Southwestern Tengchong 204 2 6 161 189 157 1 3 186 3
Total 291 16 6 1 179 222 173 1 23 226 3
Locations Sites Pvdhps
n WT S382C A383G M399I K512M/T/E A553Gb E571Q
Northeastern Dandong 8 5 3
Central Suining 16 16
Southwestern Nyingchi 25 23 1 1
Southern Hainan 26 24 1 1
Southwestern Yingjiang 58 29 1 29 1 9
Southwestern Tengchong 216 14 40 202 5 155 1
Total 349 111 41 233 5 6 164 1
Tab.1  Distribution of point mutations in Pvdhfr and Pvdhps from P. vivax isolates in China
Haplotypes Total
(n)		 Prevalence
(%)		 Temperate region Subtropical region P value
Dandong Suining Nyingchi Yingjiang Tengchong Hainan
Pvdhfr Total 291 　 7 16 3 58 204 3
Wild-type 16 5.5 　 　 　 　 　
I13A15F57 S58 T61R76H99S117I173 16 5.5 10 1 3 2 　 <0.0001
Single mutant 24 8.2 　 　 　 　 　
I13A15F57 R58T61R76H99S117I173 2 0.7 　 1 　 1 　 0.1727
I13A15F57 S58T61R76H99N117I173 1 0.3 1 　 　 　 　 0.0903
I13A15F57 S58T61R76S99S117I173 21 7.2 1 　 　 17 3 　 0.7051
Double mutant 8 2.7 　 　 　 　 　
I13A15F57R58T61R76H99N117I173 4 1.4 　 1 　 　 3 0.3165
I13A15L57R58T61R76H99S117I173 4 1.4 　 　 　 4 　 0.6835
Quadruple mutant 85 29.2 　 　 　 　 　
I13A15L57R58M61R76H99T117I173 85 29.2 　 　 5 80 　 0.0005a
Quintuple mutant 88 30.2 　 　 　 　 　
I13A15I57R58M61R76S99T117I173 82 28.2 　 　 11 71 　 0.0007a
L13A15L57R58M61R76H99T117I173 6 2.1 　 　 　 6 　 0.5639
Tandem repeat with mutant 70 24.1 　 　 　 　 　
I13A15F57 S58T61R76_S117I173 20 6.9 2 　 　 10 8 　 0.6989
I13A15F57S58T61R76_N117I173 8 2.7 1 5 　 　 2 　 <0.0001
I13A15L57S58T61R76_S117I173 2 0.7 2 　 　 　 　 　 0.0079
I13A15F57R58T61R76_N117I173 36 12.4 　 　 12 24 　 0.0555
I13V15F57S58T61R76_T117I173 1 0.3 1 　 　 　 　 　 0.0903
I13A15F57R58T61R76_N117L173 3 1.0 　 　 　 　 3 　 0.7521
Pvdhps Total 349 8 16 25 58 216 26
Wild-type 111 31.8
S382A383M399K512A553E571 111 31.8 5 16 23 29 14 24 <0.0001a
Single mutant 54 15.5
S382A383I399K512A553E571 5 1.4 3 1 1 0.0016
S382G383M399K512A553E571 49 14.0 1 20 27 1 0.0091a
Double mutant 157 45.0
C382G383M399K512A553E571 19 5.4 19 0.0881
S382G383M399K512A553Q571 1 0.3 1 0.8596
S382G383M399K512G553E571 137 39.3 8 129 <0.0001a
Triple mutant 26 7.4
C382G383M399K512G553E571 21 6.0 21 0.0548
S382G383M399M512G553E571 3 0.9 3 0.6343
S382G383M399T512G553E571 2 0.6 2 0.7386
Quadruple mutant 1 0.3
C382G383M399E512G553E571 1 0.3 1 0.8596
Tab.2  Haplotypes of Pvdhfr and Pvdhps in P. vivax isolates in China
Fig.1  Tandem repeat variation between amino acid positions 86 and 105 in the Pvdhfr gene.
Pvdhfr Pvdhps Haplotype of Pvdhfr/Pvdhps Dandong
n = 7		 Suining
n = 16		 Nyingchi
n = 1		 Hainan
n = 3		 Yingjiang
n = 58		 Tengchong
n = 195		 Total
(n)		 Prevalence
(%)
57 58 61 117 173 382 383 512 553
F S T S I S A K A WT/WT 3 10 1 　 13 10 37 13.2
F S T N I S A K A N117/WT 1 6 7 2.5
F S T T I S A K A T117/WT 1 1 0.4
L S T S I S A K A L57/WT 2 2 0.7
F R T N I S A K A R58N117/WT 3 9 12 4.3
I R M T I S A K A I57R58M61T117/WT 5 1 6 2.1
L R M T I S A K A L57R58M61T117/WT 2 2 4 1.4
F S T S I S G K A WT/G383 17 17 6.1
F R T N I S G K A R58N117/G383 1 5 6 2.1
I R M T I S G K A I57R58M61T117/G383 1 5 6 2.1
L R M T I S G K A L57R58M61T117/G383 1 13 14 5.0
L R T S I S G K A L57R58/G383 3 3 1.1
F S T N I S G K G N117/G383 1 1 0.4
F R T N I S G K G R58N117/G383G553 2 12 14 5.0
F S/R T S I S G K G S/R58/G383G553 1 1 0.4
F R T N L S G K G R58N117L173/G383G553 3 3 1.1
I R M T I S G K G I57R58M61T117/G383G553 　 　 　 　 5 46 51 18.2
I R M T I S G K A/G 1 1 0.4
L R M T I S G K G L57R58M61T117/G383G553 　 　 　 　 1 48 49 17.5
L R M T I S G K A/G 1 1 0.4
F R T N I C G K A R58N117/C382G383 1 1 0.4
I R M T I C G K A I57R58M61T117/C382G383 6 6 2.1
L R M T I C G K A L57R58M61T117/C382G383 10 10 3.6
F S T S I C G K G WT/C382G383G553 1 1 0.4
F R T N I C G K G R58N117/C382G383G553 1 1 0.4
L R T S I C G K G L57R58/C382G383G553 1 1 0.4
L R M T I C G K G L57R58M61T117/C382G383G553 8 8 2.9
I R M T I C G K G I57R58M61T117/C382G383G553 10 10 3.6
F R T N I S G M G R58N117/G383M512G553 2 2 0.7
F S T N I S G M G N117/G383M512G553 1 1 0.4
L R M T I S G T G I57R58M61T117/C382G383G553 1 1 0.4
I R M T I S G T G L57R58M61T117/G383T512G553 1 1 0.4
L R M T I C G E G I57R58M61T117/C382G383T512G553 1 1 0.4
Tab.3  Combination of Pvdhfr and Pvdhfr mutations in P. vivax isolates in China
Fig.2  Principal component analysis of combined SNPs in the Pvdhfr and Pvdhps genes of P. vivax isolates from different sites.
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