Bereckzy, S

Bjorkman, A

Djadid, ND

Gil, José Pedro

Zakeri, S

The Journal of Infectious Diseases

English

Sedigheh Zakeri

J. Pedro Gil

Sandor Bereckzy

Navid D. Djadid

Anders Bjorkman

Crossref

High Prevalence of Double
                    Plasmodium falciparum dhfr

Sapientia

1828 • JID 2003:187 (1 June) • CORRESPONDENCETable 1. Frequencies of Plasmodium falciparum dhfr and dhps genotypes of malaria patients in the Sistan-Baluchistan Province,Iran.Codon analysisscheme(Pfdhfr/Pfdhps)Totalno. ofpatients F score (95% CI)Genotype, no. of patients108R 51S59S 437S540S108R 51S59R/S 437S540S108R/S 51S59R 437S540S108R 51S59R 437S540S108R 51R/S59R 437S540S108R 51S59R 437R/S540S108R 51S59R 437R540S108R 51R/S59R 437R/S540SSingle/wild 3 0.030 (0.062–0.854) 3 0 0 0 0 0 0 0Double/wild 78 0.772 (0.0690–0.854) 0 2 4 72 0 0 0 0Triple/wild 4 0.040 (0.011–0.098) 0 0 0 0 4 0 0 0Double/single 15 0.149 (0.079–0.218) 0 0 0 0 0 14 1 0Triple/single 1 0.009 (0.003–0.054) 0 0 0 0 0 0 0 1NOTE. The codon analysis scheme follows the proposal of Kublin et al. [3]. CI, confidence interval; R, resistance-associated allele; R/S, mixed allele; S,sensitivity-associated allele.4. Furtado MR, Callaway DS, Phair JP, et al. Per-sistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receivingpotent antiretroviral therapy. N Engl J Med1999; 340:1614–22.5. Chun TW, Justement JS, Pandya P, et al. Re-lationship between the size of the human im-munodeficiency virus type 1 (HIV-1) reservoirin peripheral blood CD4+ T cells and CD4+:CD8+ T cell ratios in aviremic HIV-1–infectedindividuals receiving long-term highly activeantiretroviral therapy. J Infect Dis 2002; 185:1672–6.6. Kostrikis LG, Touloumi G, Karanicolas R, et al.Quantitation of human immunodeficiency vi-rus type 1 DNA forms with the second templateswitch in peripheral blood cells predicts diseaseprogression independently of plasma RNAload. J Virol 2002; 76:10099–108.7. Riva E, Pistello M, Narciso P, et al. Decay of HIV-1 DNA and development of drug-resistant mu-tants in patients with primary HIV-1 infectionreceiving highly antiretroviral therapy. AIDS ResHum Retroviruses 2001; 17: 1599–1604.8. StataCorp. Stata Statistical Software: release 7.0.College Station, TX: Stata Corporation, 2001.a Study group members are listed after the text.Reprints or correspondence: Dr. Guido Antonelli, Dept. of Ex-perimental Medicine and Pathology, Virology Section, University“La Sapienza,” Viale di Porta Tiburtina n. 28, 00185 Rome, Italy(guido.antonelli@uniroma1.it).The Journal of Infectious Diseases 2003; 187:1826–8 2003 by the Infectious Diseases Society of America. Allrights reserved. 0022-1899/2003/18711-0020$15.00High Prevalence of DoublePlasmodium falciparumdhfr Mutations at Codons108 and 59 in the Sistan-Baluchistan Province, IranTo the Editor—In Iran, transmission ofPlasmodium falciparum malaria mainlyoccurs in the Sistan-Baluchistan province,where 190% of the annual cases are ob-served [1]. Chloroquine is recommend-ed as the first-line antimalarial treatment,and sulfadoxine-pyrimethamine (SP) isrecommended as the second-line treat-ment. SP appears to be effective in theregion, although findings of in vivo andin vitro resistance in some small-scale, lo-cal drug resistance studies have alreadybeen documented [2]. However, SP re-sistance has been consistently reportedamong Afghan refugee settlements alongthe western border of Pakistan [3], a re-gion from which human migration re-cently has increased substantially. Thisraises the concern that SP-resistant ma-laria parasites are now invading the near-by regions of Iran.Mutations in the P. falciparum dhfr anddhps genes represent a valuable tool forepidemiological surveillance of SP resis-tance in the region, as has been sugges-ed elsewhere for another setting in whichmalaria is endemic [4]. This is supportedby a positive correlation between muta-tions in the dhfr and dhps genes and invivo SP resistance observed in a prelimi-nary study in the Iranian coastal provinceof Hormozgan [5].To evaluate the present status of thesegenes in the Sistan-Baluchistan province,we have studied the dhfr (Ser108Asn,Asn51Ile, and Cys59Arg) and dhps(Ala437Gly and Lys540Glu) single-nucle-otide polymorphism (SNP) frequencies in101 symptomatic patients with micro-scopically confirmed P. falciparum malariaattending the Chahbahar Health Center.The patients were all permanent residentsin the province; a large fraction of themwere foreigners, mostly of Afghan origin.Blood samples were obtained after writ-ten consent was given. DNA was extractedthrough phenol-chloroform–based pro-tocols. Established polymerase chain re-action–restriction fragment–length poly-morphism methods [6, 7] were performedfor the analysis of the selected SNPs.Most patients (97%) were found to si-multaneously carry the Ser108Asn andCys59Arg pyrimethamine resistance–as-sociated mutations, mainly in “pure form”[4], while retaining a wild-type mutationat position 51 (table 1). The Asn51Ile mu-tation was present in only 6 samples (6%).A similar pattern was also found in an-other small study of blood samples fromPakistan [8], which suggests that a re-gional mutation selection profile exists,with Cys59Arg mutations preceding al-terations in codon 51 toward the triplemutant.P. falciparum dhps Ala437Gly–carryingalleles were found in 17% of the patients,mostly in mixed form. This result was incontrast to previous observations of nomutations in P. falciparum dhps in a re-gion of Pakistan [8], which suggests thatthese are recent mutation selection events,possibly specific to Iranian malaria set-tings. Of note, the 437Gly mutation wassignificantly more frequent among Irani-ans (13/42 patients [30.9%]), comparedwith patients of Afghan origin (3/54 sam-Downloaded from https://academic.oup.com/jid/article-abstract/187/11/1828/886951 by B-On Consortium Portugal user on 16 July 2019CORRESPONDENCE • JID 2003:187 (1 June) • 1829ples [5.5%]; ; ). The ab-2x p 9.219 P ! .01sence of mutations at the 540 position onP. falciparum dhps reinforces the view thatthese mutations represent, in most cases,a last step toward the quintuple mutant,recently considered to be a landmark ofSP resistance [4].In conclusion, these molecular datasuggest that the high prevalence of mu-tations in the dhfr and dhps genes mightlead toward a development of SP resis-tance in the southeastern Iranian prov-inces. The remoteness of these regions,which is associated with the potentialfor rapid establishment of SP resistance,stresses the need for continuing epide-miological surveillance, including the useof molecular methods, as proposed else-where [4].Sedigheh Zakeri,1 J. Pedro Gil,2,3Sandor Bereckzy,2 Navid D. Djadid,1and Anders Bjorkman21Department of Biotechnology, Malaria ResearchUnit, Pasteur Institute of Iran, Teheran, Iran;2Department of Medicine, Malaria Research Unit,Karolinska Hospital, Karolinska Institute, Stockholm,Sweden; 3Centre for Molecular and StructuralBiomedicine, Faculdade de Cieˆncias e Tecnologia,Universidade do Algarve, Algarve, PortugalReferences1. Zakeri S, Najafabadi S, Zare A, Djadid N. De-tection of malaria parasites by nested PCR insouth-eastern, Iran: evidence of highly mixedinfections in Chahbahar district. Malar J 2002;1:2.2. Edrissian GH, Afshar A, Sayedzadeh A, Mohs-seni G, Satvat MT. Assessment of the responsein vivo and in vitro of Plasmodium falciparumto sulfadoxine-pyrimethamine in the malariousareas of Iran. J Trop Med Hyg 1993; 96:237–40.3. Rowland M, Durrani N, Hewitt S, Sondorp E.Resistance of falciparum malaria to chloroquineand sulfadoxine-pyrimethamine in Afghan ref-ugee settlements in western Pakistan: surveys bythe general health services using a simplified invivo test. Trop Med Int Health 1997; 2:1049–56.4. Kublin JG, Dzinjalamala FK, Kamwendo DD,et al. Molecular markers for failure of sulfadox-ine-pyrimethamine and chlorproguanil-dap-sone treatment of Plasmodium falciparum ma-laria. J Infect Dis 2002; 185:380–8.5. Eskandarian AA, Keshavarz H, Basco LK,Mahboudi F. Do mutations in Plasmodiumfalciparum dihydropteroate synthase and dihy-drofolate reductase confer resistance to sulfa-doxine-pyrimethamine in Iran? Trans R SocTrop Med Hyg 2002; 96:96–8.6. Duraisingh MT, Curtis J, Warhurst DC. Plas-modium falciparum: detection of polymorphismsin the dihydrofolate reductase and dihydropter-oate synthetase genes by PCR and restriction di-gestion. Exp Parasitol 1998; 89:1–8.7. Masimirembwa CM, Phuong-dung N, PhucBQ, et al. Molecular epidemiology of Plasmo-dium falciparum antifolate resistance in Viet-nam: genotyping for resistance variants of dihy-dropteroate synthase and dihydrofolate reduc-tase. Int J Antimicrob Agents 1999; 12:203–11.8. Wang P, Lee CS, Bayoumi R, et al. Resistance toantifolates in Plasmodium falciparum monitoredby sequence analysis of dihydropteroate synthe-tase and dihydrofolate reductase alleles in a largenumber of field samples of diverse origins. MolBiochem Parasitol 1997; 89:161–77.Reprints or correspondence: Dr. Sedigheh Zakeri, Malaria Re-search Unit, Dept. of Biotechnology, Pasteur Institute of Iran,PO Box 13164, Tehran, Iran (azad@institute.pasteur.ac.ir).The Journal of Infectious Diseases 2003;187:1828–9 2003 by the Infectious Diseases Society of America. Allrights reserved. 0022-1899/2003/18711-0021$15.00Downloaded from https://academic.oup.com/jid/article-abstract/187/11/1828/886951 by B-On Consortium Portugal user on 16 July 2019

High prevalence of double Plasmodium falciparum dhfr mutations at codons 108 and 59 in the Sistan-Baluchistan province, Iran

Universidade do Algarve

https://sapientia.ualg.pt/bitstream/10400.1/11589/1/handle11589.pdf

High prevalence of double Plasmodium falciparum dhfr mutations at codons 108 and 59 in the Sistan-Baluchistan province, Iran

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