Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007–2012

Abstract

BackgroundThe recent emergence and spread of artemisinin resistance in the Greater Mekong Subregion poses a great threat to malaria control and elimination. A K13-propeller gene (K13), PF3D7_1343700, has been associated lately with artemisinin resistance both in vitro and in vivo. This study aimed to investigate the K13 polymorphisms in Plasmodium falciparum parasites from the China-Myanmar border area where artemisinin use has the longest history.MethodsA total of 180 archived P. falciparum isolates containing 191 parasite clones, mainly collected in 2007–2012 from the China-Myanmar area, were used to obtain the full-length K13 gene sequences.ResultsSeventeen point mutations were identified in 46.1% (88/191) parasite clones, of which seven were new. The F446I mutation predominated in 27.2% of the parasite clones. The C580Y mutation that is correlated with artemisinin resistance was detected at a low frequency of 1.6%. Collectively, 43.1% of the parasite clones contained point mutations in the kelch domain of the K13 gene. Moreover, there was a trend of increase in the frequency of parasites carrying kelch domain mutations through the years of sample collection. In addition, a microsatellite variation in the N-terminus of the K13 protein was found to have reached a high frequency (69.1%).ConclusionsThis study documented the presence of mutations in the K13 gene in parasite populations from the China-Myanmar border. Mutations present in the kelch domain have become prevalent (>40%). A predominant mutation F446I and a prevalent microsatellite variation in the N-terminus were identified, but their importance in artemisinin resistance remains to be elucidated.

Clinical Efficacy of Dihydroartemisinin–Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria at the China–Myanmar Border

“…Besides, our recent analysis of the K13 gene in longitudinally collected samples from this study area showed increasing prevalence of parasites carrying mutations in the kelch domain, suggesting artemisinin resistance may also be evolving in this area. 34 Furthermore, given the recently documented failure of DP in Cambodia, continuous monitoring of clinical efficacy of ACT is warranted to deter the emergence and contain the potential spread of artemisinin resistance. …”

K13-Propeller Polymorphisms in Plasmodium falciparum Isolates from Patients in Mayotte in 2013 and 2014

“…A mutation in codon 554 has also been found in one isolate each from Kenya (15), Mali (16), and Senegal (unpublished data). The F495L mutation has been found in two isolates from the China-Myanmar border (17).…”

K13 Kelch Propeller Domain and mdr1 Sequence Polymorphism in Field Isolates From Northeast Region, India

“…Amino acid mutations, i.e., A676D and H719N (near 675 and 720 codons, respectively), of K13 propeller blade VI have been described recently from China-Myanmar border in low frequencies. 16 Despite the actual role, we assume that D702N mutation might have emerged independently in this region and further evidence in future will unlock an approach for validation of its role in artemisinin resistance. However, A675V allele has been observed in frequency next to A481V allele.…”

“…More precisely, it has been explained that C580Y, F446I, and P574L mutations along with other mutations in kelch propeller domain associated with artemisinin resistance are collectively spreading in a rapid manner towards upper Myanmar and extending up to regions near India. 16 Also, F446I mutation has been considered as the most prevalent in China-Myanmar border than other mutations. 24 Recently, G533A novel mutation has been reported in P. falciparum isolates of Northeast region, India along with other non-synonymous S549Y,…”

“…8 But accumulation of data over time suggests that mutations in this gene vary geographically and mostly in accordance with the employed antimalarial regimens. [14][15][16][17][18][19][20][21] In a recent study, non-reference K13 mutations viz., 584V, 580Y, 574L, 568G, 553L, 543T, 539T, 493H, 481V, 449A, 255K, and 189T have been found involved in prolonged parasite clearance, and it was also stated that artemisinin resistance in SEA has emerged independently without sweeping from Cambodia. 22 In 2016, most of them became either validated or candidate K13 mutation for artemisinin resistance.…”