Sequence analysis of coding DNA fragments of pfcrt and pfmdr-1 genes in Plasmodium falciparum isolates from Odisha, India

Sutar, Sasmita Kumari Das; Gupta, Bhavna; Ranjit, Manoranjan; Kar, Shantanu Kumar; Das, Ashim

doi:10.1590/s0074-02762011000100013

Cited by 19 publications

(24 citation statements)

References 42 publications

(56 reference statements)

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“…However, in other Indian states this haplotype is very rarely found (Mishra et al, 2006; Mixson-Hayden et al, 2010). Similarly, the C 72 V 73 I 74 E 75 T 76 haplotype is highly prevalent, and the frequency of the S 72 V 73 M 74 N 75 T 76 haplotype is comparatively low (Table 2), reconfirming previous observations from Odisha (Okombo et al, 2014; Ramani et al, 2016; Sutar et al, 2013; Sutar et al, 2011). The skewed distributional prevalence of the C 72 V 73 I 74 E 75 T 76 haplotype is reflected by the observation of statistically significant χ² value (Table 2).…”

Section: Discussionsupporting

confidence: 86%

“…This is important, as treatment in case of failure to the antimalarial CQ and SP has now become very common in almost all malaria endemic regions of the globe including India (Cui et al, 2015; Klein, 2013). In Odisha, high level of resistance to both CQ and SP has been reported from many malarious districts including Keonjhar, Sundargarh, Anugul and Sambalpur districts (Mohanty et al, 2009; Peterson et al, 1988; Srivastava et al, 2013; Sutar et al, 2011), with no report from the Deogarh district.…”

Section: Introductionmentioning

confidence: 99%

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Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Kar

Chauhan

Nanda

et al. 2016

Infection, Genetics and Evolution

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Considering malaria as a local and focal disease, epidemiological understanding of different ecotypes of malaria can help in devising novel control measures. One of the major hurdles in malaria control lies on the evolution and dispersal of the drug-resistant malaria parasite, Plasmodium falciparum. We herewith present data on genetic variation at the Single Nucleotide Polymorphism (SNP) level in four different genes of P. falciparum (Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps) that confer resistance to different antimalarials in two different eco-epidemiological settings, i.e. Hilly-Forest (HF) and Riverine-Plain (RP), in a high malaria endemic district of Odisha state, India. Greater frequency of antimalarial resistance conferring SNPs and haplotypes was observed in all four genes in P. falciparum, and Pfdhps was the most variable gene among the four. No significant genetic differentiation could be observed in isolates from HF and RP ecotypes. Twelve novel, hitherto unreported nucleotide mutations could be observed in the Pfmdr1 and Pfdhps genes. While the Pfdhps gene presented highest haplotype diversity, the Pfcrt gene displayed the highest nucleotide diversity. When the data on all the four genes were complied, the isolates from HF ecotype were found to harbour higher average nucleotide diversity than those from RP ecotype. High and positive Tajima’s D values were obtained for the Pfcrt and Pfdhfr genes in isolates from both the HF and RP ecotypes, with statistically significant deviation from neutrality in the RP ecotype. Different pattern of Linkage Disequilibrium (LD) among SNPs located in different drug-resistant genes was found in the isolates collected from HF and RP ecotypes. Whereas in the HF ecotype, SNPs in the Pfmdr1 and Pfdhfr were significantly associated, in the RP ecotype, SNPs located in Pfcrt were associated with Pfmdr1, Pfdhfr and Pfdhps. These findings provide a baseline understanding on how different micro eco-epidemiological settings influence evolution and spread of different drug resistance alleles. Our findings further suggest that drug resistance to chloroquine and sulfadoxine-pyrimethamine is approaching fixation level, which requires urgent attention of malaria control program in India.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Kar

Chauhan

Nanda

et al. 2016

Infection, Genetics and Evolution

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“…This compensatory role is believed to be played by the Pfmdr1 gene. This hypothesis is supported by the fact that strong LD was found between variants of both the Pfcrt and Pfmdr1 genes ( Duraisingh et al 2000 , Adagut & Warhurst 2001 , Duraisingh & Refour 2005 , Mu et al 2005 , Sutar et al 2011 ). Furthermore, Pfmdr1 was observed to be non-randomly associated with the mutant Pfcrt gene and directly related to CQR to improve parasite fitness ( Ekland & Fidock 2007 ).…”

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confidence: 88%

“…In Indonesia, apart from the highly frequent SVMNT haplotype, a new haplotype, CVMNN, was found to be frequent in Lombok and Irian Jaya ( Huaman et al 2004 ). Most interestingly, India has a mixture of many CQR- Pfcrt haplotypes, which are primarily dominated by SVMNT, but also show appreciable frequencies of CVIET, CVMNT and CVIDT ( Vinayak et al 2003 , 2006 , Vathsala et al 2004 , Mittra et al 2006 , Keen et al 2007 Pati et al 2007 , Bharti et al 2009 , Mixon-Hayden et al 2010 , Awasthi et al 2011 , Sutar et al 2011 , Lumb et al 2012 ). In Pakistan, Iran and Sri Lanka, the S agt VMNT haplotype is reported at appreciable frequencies and is believed to have been imported from India ( Zakeri et al 2008 , Zhang et al 2011 , Rawasia et al.…”

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Genetics of chloroquine-resistant malaria: a haplotypic view

Awasthi¹,

Das²

2013

Mem. Inst. Oswaldo Cruz

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The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.

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“…Mutation in Plasmodium falciparum multidrug resistance 1 (pfmdr1), especially in kodon 86, where asparagin was changed into tyrosin, have been identified to modulate higher levels of CQR. 6,7 However, mutation in pmfdr1 alone is not enough to mediate CQR phenotype and that the trait is multigenic. 8 A 76-Ser to Thr polymorphism in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene, which is located on chromosome 7, is known to be an important key of CQR phenotype.…”

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Polymorphisms in the pfcrt and pfmdr1 genes in Plasmodium falciparum isolates from South Sumatera, Indonesia

2014

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Polymorphisms in the pfcrt and pfmdr1 genes in Plasmodium falciparum isolates from South Sumatera, Indonesia Abstrak Latar belakang: Selama lebih dari 10 tahun terakhir, resistensi terhadap obat antimalaria telah menjadi masalah utama bagi kesehatan masyarakat di Asia Tenggara termasuk Sumatera Selatan. Studi ini bertujuan untuk mengidentifikasi adanya polimorfisme pada gen Plasmodium falciparum yang berhubungan dengan resistensi klorokuin pada isolat P. falciparum di Lahat, Sekayu, Baturaja, dan Palembang. Metode: Studi molekuler dilakukan untuk mengidentifikasi alel mutan dua gen yang berhubungan dengan resistensi klorokuin pada isolat P. falciparum di Sumatera Selatan. Sebanyak 25 pasien diambil darahnya, kemudian dilakukan isolasi DNA. Susunan dari kedua gen (Plasmodium falciparum chloroquine resistance transporter/pfcrt dan Plasmodium falciparum multidrug resistance/pfmdr1) dianalisis dengan menggunakan polymerase chain reaction (PCR) dan restriction fragment length polymorphism (RFLP). Hasil: Polimorfisme pada pfcrt 76-Thr dan pfmdr1 86-Tyr ditemukan pada semua isolat. Temuan ini menjelaskan terjadinya kegagalan pengobatan dengan klorokuin dalam beberapa tahun terakhir di Sumatera Selatan. Kesimpulan: Penelitian ini menguatkan bahwa PCR-RFLP merupakan cara sederhana dan cepat untuk mendeteksi polimorfisme pada gen yang dapat memprediksi chloroquine resistance (CQR). Walaupun adanya polimorfisme pada gen pfcrt dan pfmdr1 merupakan penanda CQR yang bermakna, perlu penelitian lebih lanjut mengenai peran polimorfisme ini pada respons obat in vivo dan in vitro. AbstractBackground: Over the past decade, antimalarial drug resistance has rapidly become a major public health problem in South East Asia region including South Sumatra. This study aimed to determine the extent of gene polymorphisms associated with chloroquine resistance (CQR) in P. falciparum isolates from Lahat, Sekayu, Baturaja and Palembang district. Methods:A molecular study was conducted to identify the mutant alleles of the genes associated with the resistance to chloroquine among the isolates of Plasmodium falciparum from South Sumatera. Blood from 25 patients was collected, DNA was isolated, and the sequences of two different genes (Plasmodium falciparum chloroquine resistance transporter/pfcrt and Plasmodium falciparum multidrug resistance/pfmdr1) were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Results:This study identified polymorphism in the pfcrt 76-Thr in all isolates and pfmdr1 86-Tyr. These findings may reflect the failure of treatment with the standard dose of chloroquine within the last few years in South Sumatera.Conclusion: PCR-RFLP technique provide a simple and rapid method of detecting polymorphisms in genes that may predict chloroquine resistance (CQR). Although the identification of the polymorphism in the pfcrt and pfmdr1 genes provides a significant indicator of CQR, further studies are needed to determine the role of these polymorphisms in the in vivo and in vitro respon...

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Sequence analysis of coding DNA fragments of pfcrt and pfmdr-1 genes in Plasmodium falciparum isolates from Odisha, India

Cited by 19 publications

References 42 publications

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Genetics of chloroquine-resistant malaria: a haplotypic view

Polymorphisms in the<em> pfcrt</em> and <em>pfmdr1</em> genes in <em>Plasmodium falciparum</em> isolates from South Sumatera, Indonesia

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