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Role of S180L polymorphism in etiology of malaria caused by Plasmodium falciparum in a small group of Pakistani population.

ABSTRACT: The aim of our study was to investigate the role of S180L polymorphism in modulation of acquisition of malaria caused by Plasmodium falciparum in a small group of Pakistani population. A total of 133 individuals including 60 controls and 73 patients of malaria, caused by Plasmodium falciparum, were genotyped using allele-specific PCR. Ninety-two samples successfully demonstrated the PCR amplification results, while forty-one samples could not be genotyped due to failure in PCR amplification. The allele frequency for S180L polymorphism was deviant from Hardy-Weinberg equilibrium (HWE) of the population under observation. Association was found between the observed polymorphism and the occurrence of malaria caused by Plasmodium falciparum (p = 0.01). Chances of malaria caused by Plasmodium falciparum were low in CC genotype carriers in comparison to other genotypes (Odds ratio: 0.3016; 95% CI: 0.124-0.729). The present findings suggest that S180L polymorphism is important in modulating the probability of acquisition of malaria caused by Plasmodium falciparum in Pakistani population. The CC genotype plays a protective role in local population against this type of malaria.

SUBMITTER: Nawaz SK

PROVIDER: S-EPMC4690437 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Role of S180L polymorphism in etiology of malaria caused by Plasmodium falciparum in a small group of Pakistani population.

Nawaz Syed Kashif SK Ahmed Bisma B Arshad Najma N Rani Asima A Rasool Hamadia H Arshad Muhammad M

Bosnian journal of basic medical sciences 20150819 4

The aim of our study was to investigate the role of S180L polymorphism in modulation of acquisition of malaria caused by Plasmodium falciparum in a small group of Pakistani population. A total of 133 individuals including 60 controls and 73 patients of malaria, caused by Plasmodium falciparum, were genotyped using allele-specific PCR. Ninety-two samples successfully demonstrated the PCR amplification results, while forty-one samples could not be genotyped due to failure in PCR amplification. The ...[more]

PMID: 26614847

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Project description:Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data. Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD). The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86 k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes. The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia. Tajima's D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens.

Project description:Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance.In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)

Dataset Information

Role of S180L polymorphism in etiology of malaria caused by Plasmodium falciparum in a small group of Pakistani population.

Publications

Role of S180L polymorphism in etiology of malaria caused by Plasmodium falciparum in a small group of Pakistani population.

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