Limited genetic diversity in the PvK12 Kelch protein in Plasmodium vivax isolates from Southeast Asia

Abstract

BackgroundArtemisinin resistance in Plasmodium falciparum has emerged as a major threat for malaria control and elimination worldwide. Mutations in the Kelch propeller domain of PfK13 are the only known molecular markers for artemisinin resistance in this parasite. Over 100 non-synonymous mutations have been identified in PfK13 from various malaria endemic regions. This study aimed to investigate the genetic diversity of PvK12, the Plasmodium vivax ortholog of PfK13, in parasite populations from Southeast Asia, where artemisinin resistance in P. falciparum has emerged.MethodsThe PvK12 sequences in 120 P. vivax isolates collected from Thailand (22), Myanmar (32) and China (66) between 2004 and 2008 were obtained and 353 PvK12 sequences from worldwide populations were retrieved for further analysis.ResultsThese PvK12 sequences revealed a very low level of genetic diversity (π = 0.00003) with only three single nucleotide polymorphisms (SNPs). Of these three SNPs, only G581R is nonsynonymous. The synonymous mutation S88S is present in 3% (1/32) of the Myanmar samples, while G704G and G581R are present in 1.5% (1/66) and 3% (2/66) of the samples from China, respectively. None of the mutations observed in the P. vivax samples were associated with artemisinin resistance in P. falciparum. Furthermore, analysis of 473 PvK12 sequences from twelve worldwide P. vivax populations confirmed the very limited polymorphism in this gene and detected only five distinct haplotypes.ConclusionsThe PvK12 sequences from global P. vivax populations displayed very limited genetic diversity indicating low levels of baseline polymorphisms of PvK12 in these areas.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1583-0) contains supplementary material, which is available to authorized users.

Polymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination Therapies

“…Unfortunately, due to a lack of samples, we could not examine Kelch 12 from PNG parasites. The limited polymorphisms observed in this Pacific sample set agree with findings in Southeast Asia (52,54).…”

The prevalence of molecular markers of drug resistance in Plasmodium vivax from the border regions of Thailand in 2008 and 2014

“…There appears to be selection acting on these mutations in the Greater Mekong Region, as their prevalence has increased throughout the years artemisinin has been used. The situation in P. vivax is, however, much less clear, with genetic diversity observed in the orthologous Pvk12 gene ( Popovici et al, 2015 ; Deng et al, 2016 ; Pearson et al, 2016 ; Wang et al, 2016 ).…”

“…Artemisinin resistance in P. falciparum is linked to mutations in the Kelch 13 ( Pfk13 ) gene, and high prevalences of mutant alleles have been observed in Southeast Asia ( Ashley et al, 2014 ; Menard et al, 2016 ). There are limited studies on the prevalence of mutations in the P. vivax orthologue of this gene ( Pvk12 ), although three studies that looked for polymorphisms at this locus from samples collected in Southeast Asia between 2008 and 2013 suggest that there is limited polymorphism present ( Popovici et al, 2015 ; Deng et al, 2016 ; Wang et al, 2016 ).…”

A Review: Artemisinin-Based Combination Therapies [ACTs] and K13 Polymorphism

“…Artemisinin-Based Combination Therapies (ACTs) are the best available treatment for P. falciparum malaria [23]. The impact of the use of ACTs for malaria treatment is proven by the fact that Miss TuYouyou was awarded the 2015 Nobel Prize for Medicine for the discovery of the malaria drug, Artemisinin [28]. Numerous studies have been reported to determine the levels of polymorphisms of K13 in this region in order to map the spread and evolution of ART resistance [29].…”