Polymorphism analysis of pfmdr1 gene in Plasmodium falciparum isolates 11 years post-adoption of artemisinin-based combination therapy in Saudi Arabia

Al-Mekhlafi, Hesham M.; Madkhali, Aymen M; Atroosh, Wahib M.; Ghzwani, Ahmad Hassn; Zain, Khalid Ammash; Ghailan, Khalid Y.; Hamali, Hassan A; Mobarki, Abdullah A; Alharazi, Talal; Eisa, Zaki M.; Lau, Yee Ling

doi:10.1038/s41598-021-04450-x

Cited by 3 publications

(7 citation statements)

References 64 publications

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“…At codon N1042D, no mutation was observed in clinical isolates collected from west Ethiopia. The absence of mutation at this codon was previously reported from Southeast Iran [51],Saudi Araba [23]and Vanuatu and Solomon Islands [52].However, the nding was in contrast to studies from South America that reported mutation of the N1042D [21,53], and this SNP contributes to resistance to quinine [54].Therefore, distribution of pfmdr1-N1042D mutation might differ over different geographic areas due to the discrepancy in the genetic variation of the parasites and the type of stress that each strain had experienced. It also demonstrates the low or no contribution of the N1042D mutation to antimalarial drug pressure in the study area.…”

Section: Discussionsupporting

confidence: 51%

“…N86Y mutation increases parasite susceptibility to the partner drugs lumefantrine and me oquine and the active artemisinin metabolite dihydroartemisinin and conversely augments resistance to the ACT partner drug amodiaquine and the former rst-line agent CQ [20]. Studies from malaria endemic sites have reported a signi cant increase in the wild-type pfmdr1 N86 and D1246 following ACT [8,23]. The pfmdr1, NFD haplotype (codons N86, 184F and D1246), has been associated with reduced sensitivity to lumefantrine [24] and a temporal increase in the Pfmdr1 NFD haplotype was reported from different parts of Africa [25,26].…”

Section: Introductionmentioning

confidence: 99%

“…Measuring the prevalence of pfmdr1 polymorphisms has implications for designing policies such as drug cycling, sequential ACT treatments or multiple rst-line therapies [23]. Moreover, monitoring of drug resistance in Plasmodium populations is crucial for malaria control and elimination [2].…”

Section: Introductionmentioning

confidence: 99%

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Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

Tadele

Jawara

Oboh

et al. 2023

Preprint

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Background Chloroquine which was the first-line drug for the treatment of uncomplicated P. falciparum malaria in Ethiopia was officially abandoned in 1998, and replaced by sulphadoxine-pyrimethamine which in turn was replaced by artemether-lumefantrine (AL) in 2004. Pfcrt gene has been associated with chloroquine resistance and pfmdr1 gene can alter malaria parasite susceptibility to most of the current antimalarial drugs, including lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of AL for eighteen years, we determined polymorphisms of pfcrt haplotype and pfmdr1 SNPs in two sites of West Ethiopia with different levels of malaria transmission. Methods Health-facility based cross-sectional study was conducted at Assosa and Anger Gute areas. Finger-prick blood samples were collected from a total of 225 microscopically confirmed Plasmodium falciparum patients and spotted onto Whatman filter papers. For molecular genotyping, parasite DNA was extracted using the Chelex extraction method. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes at positions 72–76 and pfmdr1 SNPs at codon N86Y, Y184F, N1042D and D1246Y. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A p-value of less or equal to 0.05 was considered significant. Results Of the 225 samples, 95.5%, 94.4%, 86.7%, 91.1% and 94.2% samples were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. A total of 46.5%( 100/215) of the clinical isolates in west Ethiopia carry the mutant pfcrt genotype. The mutant haplotypes was detected among 33.5% (52/ 155) and 80% (48/60) of isolates collected from the Assosa and Anger Gute sites, respectively. P. falciparum with chloroquine-resistant haplotypes were more prevalent in the Anger Gute area (low transmission site) as compared with the Assosa area (high transmission area)(COR = 8.4, P = 0.00). Pfmdr1- N86Y wild type and 184F mutations were found in 79.8%( 166/208) and 73.4% (146 /199) samples, respectively. No single mutation was observed at pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codonsN86Y- Y184F-D1246Y were identified with the dominant NFD 61% (122/200) followed by the wild type NYD haplotype (17%( 34/200). The proportion of parasites with multiple pfmdr1 copies was 8.4%( 19/225). There was no difference in the distribution of pfmdr1 SNPs, haplotypes and CNV between the two study sites (P > 0.05). Conclusion There is a gradual regaining of chloroquine-sensitive haplotype in the study areas after cessation of CQ use for the treatment of uncomplicated falciparum malaria; however, the return to the wild-type is higher in high malaria transmission site (Assosa) than in low transmission area (Anger Gute). A high prevalence of the wild-type alleles N86, D1042 and D1246 and of the mutant-type allele 184F was detected from both study sites. The NFD haplotype was the predominant haplotype of the N86Y-Y184F-D1246Y and 8.4% of the parasites carry multiple copies of the pfmdr1 gene. Continuous surveillance is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

Tadele

Jawara

Oboh

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…N86Y mutation increases parasite susceptibility to the partner drugs lumefantrine and mefloquine and the active artemisinin metabolite dihydroartemisinin and conversely augments resistance to the ACT partner drug amodiaquine and the former first-line agent CQ [ 19 ]. Studies from malaria endemic sites have reported a significant increase in the wild-type pfmdr1 N86 and D1246 following ACT [ 8 , 22 ]. The pfmdr1, NFD haplotype (codons N86, 184F and D1246), has been associated with reduced sensitivity to lumefantrine [ 23 ] and a temporal increase in the Pfmdr1 NFD haplotype was reported from different parts of Africa [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…Measuring the prevalence of pfmdr1 polymorphisms has implications for designing policies such as drug cycling, sequential artemisinin-based combination treatments or multiple first-line therapies [ 22 ]. Moreover, monitoring of drug resistance in Plasmodium populations is crucial for malaria control and elimination [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

Tadele

Jawara

Oboh

et al. 2023

Malar J

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Background Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether–lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission. Methods 230 microscopically confirmed P. falciparum isolates were collected from Assosa (high transmission area) and Gida Ayana (low transmission area) sites, of which 225 of them tested positive by PCR. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes and pfmdr1 SNPs. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A P-value of less or equal to 0.05 was considered significant. Results Of the 225 samples, 95.5%, 94.4%, 86.7%, 91.1%, and 94.2% were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. The mutant pfcrt haplotypes were detected among 33.5% (52/155) and 80% (48/60) of isolates collected from the Assosa and Gida Ayana sites, respectively. Plasmodium falciparum with chloroquine-resistant haplotypes was more prevalent in the Gida Ayana area compared with the Assosa area (COR = 8.4, P = 0.00). Pfmdr1-N86Y wild type and 184F mutations were found in 79.8% (166/208) and 73.4% (146/199) samples, respectively. No single mutation was observed at the pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codons N86Y–Y184F–D1246Y were identified with the dominant NFD 61% (122/200). There was no difference in the distribution of pfmdr1 SNPs, haplotypes, and CNV between the two study sites (P > 0.05). Conclusion Plasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. The NFD haplotype was the predominant haplotype of the N86Y–Y184F–D1246Y. A continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.

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Association between interleukin-27 gene polymorphisms and Plasmodium falciparum Malaria

et al. 2023

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Malaria is often characterized by a complicated disease course due to multifaceted intrinsic genetic factors of the host and the parasite. This study aimed to investigate the role of interleukin-27 ( IL-27) gene polymorphisms in Plasmodium falciparum malaria infection in a Saudi Arabian cohort. This case-control study obtained blood samples from 250 malaria patients with P. falciparum and 200 randomly identified healthy control subjects from the Malaria Center in the Jazan area. Malaria patients were grouped into three cohorts as follow: low (<500 parasites/µl of blood), moderate (500–1000 parasites/µl of blood), and high (>1000 parasites/µl of blood) parasitemia. The results show that the IL-27 variant rs181209 was significantly associated with malaria patients ( P = 0.026). Similarly, the homozygous GG genotype of rs26528 was also associated with risk of developing P. falciparum malaria ( P = 0.032). The minor allele C of variant rs181206 exhibited an association with low to moderate parasitemia ( P = 0.046). Furthermore, the rs181209 AA genotype was statistically significant in age group 1–5 years ( P = 0.049). In conclusion, this study suggests that variant rs181209 and rs26528 could be associated with the risk of malaria infection by P. falciparum in the population studied.

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Polymorphism analysis of pfmdr1 gene in Plasmodium falciparum isolates 11 years post-adoption of artemisinin-based combination therapy in Saudi Arabia

Cited by 3 publications

References 64 publications

Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

Clinical isolates of uncomplicated falciparum malaria from high and low malaria transmission areas show distinct pfcrt and pfmdr1 polymorphisms in western Ethiopia

Association between interleukin-27 gene polymorphisms and Plasmodium falciparum Malaria

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