2010—2018年云南中缅边境地区恶性疟原虫抗磺胺多辛-乙胺嘧啶药物基因多态性分析

doi:10.12140/j.issn.1000-7423.2024.02.004

中国寄生虫学与寄生虫病杂志 ›› 2024, Vol. 42 ›› Issue (2): 153-159.doi: 10.12140/j.issn.1000-7423.2024.02.004

2010—2018年云南中缅边境地区恶性疟原虫抗磺胺多辛-乙胺嘧啶药物基因多态性分析

燕贺¹(), 黄芳¹^,², 丰俊¹^,², 尹建海¹, 夏志贵¹, 曹建平¹^,^*()

1 中国疾病预防控制中心寄生虫病预防控制所（国家热带病研究中心）；传染病溯源预警与智能决策全国重点实验室；国家卫生健康委员会寄生虫病原与媒介生物学重点实验室；世界卫生组织热带病合作中心；国家级热带病国际联合研究中心，上海 200025
2 上海市疾病预防控制中心，上海 200051

收稿日期:2023-12-26 修回日期:2024-03-14 出版日期:2024-04-30 发布日期:2024-04-28
通讯作者: * 曹建平（1964—），男，博士，研究员，从事寄生虫感染与免疫研究。E-mail：caojp@chinacdc.cn
作者简介:燕贺（1984—），女，博士研究生，副研究员，从事疟疾病原与免疫研究工作。E-mail：yanhe@nipd.chinacdc.cn
基金资助:
上海市公共卫生体系建设三年行动计划(GWV-10.1-XK13)

Polymorphism of sulfadoxine-pyrimethemine resistant gene of Plasmodium falciparum in China-Myanmar border area from 2010 to 2018

YAN He¹(), HUANG Fang¹^,², FENG Jun¹^,², YIN Jianhai¹, XIA Zhigui¹, CAO Jianping¹^,^*()

1 National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Center for International Research on Tropical Diseases, Shanghai 200025, China
2 Shanghai Municipal Center for Diseases Control and Prevention; Shanghai 200336, China

Received:2023-12-26 Revised:2024-03-14 Online:2024-04-30 Published:2024-04-28
Contact: * E-mail: caojp@chinacdc.cn
Supported by:
Three-Year Public Health Action Plan of Shanghai(GWV-10.1-XK13)

摘要/Abstract

摘要：

目的分析云南中缅边境地区恶性疟原虫抗叶酸类药物磺胺多辛-乙胺嘧啶抗性基因的多态性和抗性回复突变趋势。方法收集2010—2018年中缅边境恶性疟病例滤纸血样品，巢式PCR扩增恶性疟原虫二氢叶酸还原酶（pfdhfr）基因和恶性疟原虫二氢蝶酸合酶（pfdhps）基因，采用Geneious Prime软件比对测序结果，Microsoft Excel 2016和GraphPad prism 8.0.2软件分析突变频率和单体型分布差异，卡方检验分析抗性相关基因位点单核苷酸多态性特征和不同年份单体型分布差异，Haploview软件分析pfdhfr和pfdhps基因连锁不平衡情况。结果共收集中缅边境地区190份恶性疟样品，PCR扩增出pfdhfr 180份、pfdhps 178份。测序结果显示，pfdhfr和pfdhps均出现等位基因的多重感染，其中pfdhfr检出17个多重感染，突变位点分别位于第51、59、108、164位氨基酸密码子，其表型为51I/59R/108N/164L；pfdhps检出4个多重感染，突变位点分别位于第436、437、540、581位氨基酸密码子，其表型为436A/437A/540E\N/581G（“\”表示并列关系）。pfdhfr第N51I、C59R、S108N、I164L位点的突变率分别为57.8%（108/187）、90.1%（172/191）、93.3%（168/180）、59.6%（109/183）；pfdhps第S436A\C、A437G、K540E\N、A581G位点抗性突变率分别为54.7%（99/181）、86.5%（154/178）、84.9%（152/177）、28.7%（51/178）。pfdhfr单体型主要集中在三点、四点突变型（51I59R108N/59R108N164L、51I59R108N164L），分别占44.9%（84/187）和36.9%（69/187）。pfdhfr和pfdhps野生型在2010年均未检出。2011年的pfdhfr三点、四点突变单体型（同上）分布频率分别为35.9%（23/64）、37.5%（24/64），均小于2010年的46.2%（30/65）、49.23%（32/65）（P < 0.05），与2014—2018年的53.4%（32/58）、22.4%（13/58）比较差异有统计学意义（P < 0.05）。2014—2018年的pfdhps三点突变单体型（436A\C437G540E\N，437G540E\N581G）分布频率为62.1%（36/58），小于2010年的82.3%（51/62）和2011年的78.7%（48/61）（均P < 0.05）。连锁不平衡分析显示，pfdhfr C59R与S108N基因关联性强（D’= 1，r² = 0.8），pfdhps S436A与A581G关联性强（D’= 1，r² = 0.6），且S108N与 K540E存在较强关联性（D’= 0.8，r² = 0.2）。结论云南中缅边境恶性疟原虫pfdhfr和pfdhps基因的抗性分子突变单体型仍是优势基因，且随着停药时间延长突变频率逐渐降低。

关键词: 恶性疟原虫, 抗叶酸耐药性, pfdhfr, pfdhps, 中缅边境

Abstract:

Objective To analyze the polymorphism of sulfadoxine-pyrimethemine (SP) resistant gene and resistance recovery mutation trend of Plasmodium falciparum in Yunnan China-Myanmar border area. Methods P. falciparum blood filter paper samples were collected from China-Myanmar border area in 2010 to 2018. The target gene fragments P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) were amplified by nest-PCR, of which the DNA sequences were aligned by Geneious Prime software. Microsoft Excel 2016 and GraphPad Pism 8.0.2 software were used to analyze the differences in mutation frequency and distribution of haplotype. Haploview software was used to analyze the linkage disequilibrium of gene 180 pfdhfr and 178 pfdhps, chi-square test was used to analyze the characteristics of single nucleotide polymorphisms at resistance-associated gene loci and the varying distribution of haplotypes in different years. Results A total of 190 P. falciparum blood filter samples were collected in China-Myanmar border area. Specifically, 180 pfdhfr and 178 pfdhps gene fragments were successfully amplified and sequenced. The mutated amino acid codon locus in pfdhfr 51, 59, 108 and 164 was changed as N51I, C59R, S108N, I164L; which in pfdhps 436, 437, 540 and 581 was changed as S436 A and C, A437G, K540E and N, A581G. The resistant site frequency in Pfdhfr N51I, C59R, S108N and I164L was respectively 57.8% (108/187), 90.1% (172/191), 93.3% (168/180), 59.6% (109/183), while in pfdhps S436A\C, A437G, K540E\N, A581G the resistant site frequency was respectively 54.7% (99/181), 86.5% (154/178), 84.9% (152/177) and 28.7% (51/178). The majority of pfdhfr genotypes were focused on triple and quadruple site mutations (51I59R108N/59R108N164L, 51I59R108N164L), with 44.9% (84/187) and 36.9% (69/187), respectively. The wild types of two genes were not detected in 2010. The triple and quadruple mutated haplotypes frequency (51I59R108N/59R108N164L, 51I59R108N164L) with 35.9% (23/64) and 37.5% (24/64) in 2011 was obviously less than in 2010 with 46.2% (30/65), 49.23% (32/65) and 53.4% (32/58), 22.4% (13/58) from the year 2014 to 2018 (P < 0.05). The pfdhps triple mutated haplotypes distribution frequency 62.1% (36/58) (436A\C437G540E\N, 437G540E\N/581G) after the year 2014 was significantly less than 82.3% (51/62) in 2010 and 78.7% (48/61) in 2011 (P < 0.05). The Linkage disequilibrium analysis between the two loci C59R and S108N in pfdhfr showed a strong association with D’ = 1 and r² = 0.8， S436A and A581G in pfdhps gene showed a strong association with D’ = 1 and r² = 0.6. Meanwhile, S108N in pfdhfr and K540E in pfdhps were associated with D’ = 0.8, r² = 0.2. Conclusion It demonstrated that P. falciparum resistant gene pfdhfr and pfdhps presented with mutated haplotype as the dominant gene in Yunnan, China-Myanmar border area, furthermore, its mutation frequency may reduce as the medication discontinuation time for the host extended.

Key words: Plasmodium falciparum, Antifolate drug resistance, pfdhfr, pfdhps, China-Myanmar border

中图分类号:

R382.312

燕贺, 黄芳, 丰俊, 尹建海, 夏志贵, 曹建平. 2010—2018年云南中缅边境地区恶性疟原虫抗磺胺多辛-乙胺嘧啶药物基因多态性分析[J]. 中国寄生虫学与寄生虫病杂志, 2024, 42(2): 153-159.

YAN He, HUANG Fang, FENG Jun, YIN Jianhai, XIA Zhigui, CAO Jianping. Polymorphism of sulfadoxine-pyrimethemine resistant gene of Plasmodium falciparum in China-Myanmar border area from 2010 to 2018[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2024, 42(2): 153-159.

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引物名称 Primer	序列 Sequence	扩增长度/bp
pfdhfrNF	TTTATGATGGAACAAGTCTGC	648
pfdhfrNR	AGTATATACATCGCTAACAGA
pfdhfrF	ACAAGTCTGCGACGTTTTCGATATTTATG	594
pfdhfrR	ATTCATATGTACTATTTATTCTAGT
pfdhpsNF	AGCAATTGCTAATCCACCTG	838
pfdhpsNR	GATTCTTTTTCAGATGGAGG
pfdhpsF	TAATCCACCTGAAAAGAAATAC	706
pfdhpsR	ATTTTTGTTGAACCTAAACGTGCTGTTCA
DHFR^a	ATTCATATGTACTATTTATTCTAGT	-
DHPS1^a	TTTTTAAACACACCACATATATT	-
DHPS2^a	ATTTCTGGATTATTTGTACAAGCAC	-

基因Gene	单倍体型 Haplotype	样品数/份 No. Isolate	频率/% Frequency/%
pfdhfr	NCSI	11	5.9
	ICSI	1	0.5
	NCNI	1	0.5
	IRSI	1	0.5
	NRNI	18	9.6
	ICNI	2	1.1
	IRNI	42	22.5
	NRNL	42	22.5
	IRNL	69	36.9
pfdhps	SAKA	15	8.3
	CAKA	1	0.6
	SAEA	3	1.7
	SGKA	2	1.1
	AAKA	1	0.6
	AAEA	4	2.2
	AGKA	4	2.2
	SGKG	3	1.7
	SGEA	12	6.7
	SAEG	1	0.6
	AGEA	78	43.3
	AGNA	8	4.4
	SGEG	40	22.2
	SGNG	7	3.9
	AGEG	1	0.6

2010—2018年云南中缅边境地区恶性疟原虫抗磺胺多辛-乙胺嘧啶药物基因多态性分析

Polymorphism of sulfadoxine-pyrimethemine resistant gene of Plasmodium falciparum in China-Myanmar border area from 2010 to 2018

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基因 Gene	突变位点 Mutant site	野生型样品数/份 No. wild isolate	突变型样品数/份 No. mutant isolate	多重感染样品数/份 No. mixed infection	突变率/% Mutation rate/%
pfdhfr	N51I^a	72	101	7	57.8
	C59R^a	13	166	6	90.1
	S108N	12	168	0	93.3
	I164L^a	70	105	4	59.6
pfdhps	S436A^a	79	95	3	54.7
	S436C		1		54.7
	A437G	24	154	0	86.5
	K540E^a	26	136	1	84.9
	K540N		15		84.9
	A581G	127	51	0	28.7

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