In ROK, there is a P. vivax-based endemic area in Gyeonggi province near the DMZ, indicating that the military personnel residing in this region are at high-risk of malaria. Since 1997, ROK Army has carried out continuous malaria chemoprophylaxis (chloroquine and primaquine) to prevent malaria against approximately 100,000 military personnel. Due to massive chemoprophylaxis, the concern of resistance is consistent.
Chloroquine and primaquine have been used worldwide as therapeutic and preventive drugs of malaria. Due to the extensive drug usage, drug insusceptibility has been reported, and studies have been performed on SNP investigation of relevant genes including Pvcrt and Pvmdr . Since 1997, ROK Army has executed massive and long-term malaria chemoprophylaxis (Chloroquine, Primaquine) near the malaria endemic regions due to concern of chemoprophylaxis-mediated resistance. Thus, the Armed Forces Medical Research Institute has conducted SNP analysis on malaria resistance-related genes, since 2012 [2, 6]. To date, although there have been P. vivax cases of resistance to chloroquine in many other areas of the world, in malaria-endemic regions of ROK, drug resistance has not been reported. However, issues including drug insusceptibility to chloroquine and rapid transition of Pvmdr SNPs have been reported. A previous study showed that Pvmdr SNP mutations of T529 (56.4%), F1076L (100%), E1233 (40%), and S1358 (3.7%) were identified in ROK army from 2011 to 2012 [6; Chung et al., 2015].
In this study, SNP profiling is dramatically changed compared with previous ROK reports. In detail, G698S, L845F, M908L, T958M, F1076L, Y541C, K44, L493, and T529 mutations in the Pvmdr-1 gene were detected in malaria-infected military personnel of ROK. Previous reports showed the F1076L mutation in the Pvmdr-1 gene in India and Afghanistan people [15, 16]. It was also reported that the F1076L mutation in the Pvmdr-1 gene has a relationship with chemoprophylaxis. For example, the high prevalence of Pvmdr-1 F1076L mutation might have influenced the efficacy of chloroquine combination with primaquine in Iran from 2001 to 2016 . Globally, various Pvmdr-1 SNPs profiles including single (T958M; Y976F), double (T958M and F1076L; Y976F and F1076L), triple (T958M, Y976F, and F1076L), quadruple (S510T, M908L, T958M, and F1076L; S513R, M908L, T958M, and F1076L), quintuple (G689S, L845F, M908L, T958M, and F1076L), sextuple (S510T, G698S, M908L, T958M, Y976F, and F1076L; S513R, G698S, M908L, T958M, Y976F, and F1076L), and septuple (S513R, I636T, G698S, M908L, T958M, Y976F, and F1076L; S513R, G698S, M908L, A829V, T958M, Y976,F and F1076L) centred on these mutations (T958M, Y976F, and F1076L). . However, K44, L493, T529, and Y541C mutations in the Pvmdr-1 gene have not been reported.
Thus, we inferred rapid transition of polymorphisms in the Pvmdr-1 gene. Fortunately, there is no resistance in the abovementioned mutations due to chloroquine-induced normal clearance of the parasite. In detail, patients with Y541C phenotypic mutation showed no resistance to chloroquine treatment, and parasitic clearance was confirmed after one month. Thus, the Y541C mutation is not related to chloroquine resistance.
In a previous study, Suwanarusk R. et al. showed the Y976F mutation to be linked to chloroquine resistance based on increase of IC50 value . Our study showed no SNP at the Y976F position. In previous research, F1076L mutation was found in all samples with Y976F mutation and was regarded as a background mutation . In cases of F1076L mutation, although Y976F mutation was not detected, these mutations observed in investigated all specimens . Based on these results, consistent surveillance of Pvmdr-1 SNPs should be performed.