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Mechanisms of Resistance

Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response

Maria Isabel Veiga, Nuno S. Osório, Pedro Eduardo Ferreira, Oscar Franzén, Sabina Dahlstrom, J. Koji Lum, Francois Nosten, José Pedro Gil
Maria Isabel Veiga
aLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
bICVS/3B's, PT Government Associate Laboratory, Guimarães, Braga, Portugal
cMalaria Research Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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  • ORCID record for Maria Isabel Veiga
Nuno S. Osório
aLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
bICVS/3B's, PT Government Associate Laboratory, Guimarães, Braga, Portugal
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Pedro Eduardo Ferreira
dSchool of Biological Sciences, Nanyang Technological University, Singapore
eDrug Resistance and Pharmacogenetics, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal
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Oscar Franzén
fDepartment of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Sabina Dahlstrom
cMalaria Research Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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J. Koji Lum
gHarpur College of Arts and Sciences, Binghamton University, The State University of New York, Binghamton, New York, USA
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Francois Nosten
hShoklo Malaria Research Unit, Mae Sot, Tak, Thailand
iFaculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
jCentre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom
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José Pedro Gil
eDrug Resistance and Pharmacogenetics, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal
gHarpur College of Arts and Sciences, Binghamton University, The State University of New York, Binghamton, New York, USA
kDivision of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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DOI: 10.1128/AAC.03337-14
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  • FIG 1
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    FIG 1

    2D representation of PfMRP2, with the location of the analyzed SNPs and microindels. The structure depicted refers to the reference P. falciparum 3D7 clone sequence, comprising 2,108 aa. Note that the numbering of amino acids follows the 3D7 reference genomic data, independently of the microindel variation observed in the studied Thai set of parasites.

  • FIG 2
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    FIG 2

    Microindels identified in the Pfmrp2 by sequencing the Thai isolates and aligning the sequences with publicly available sequencing data. The 5 microindels identified were subcategorized as MI variants of type a (the 3D7 reference genomic sequence type); the other types are designated b to l for the variants found among the Thai isolates (N) and the publicly available genomes. Symbols for publicly available genomes: £, Dd2; &, Hb3; #, UGT5.1; §, RAJ116; +, IGH-CR14. Highlighted black boxes denote amino acid positions that are described in the PlasmoDB database (http://www.plasmodb.org) as single nucleotide polymorphisms.

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    FIG 3

    SNPs and microindels and their associations with IC50 values and parasite clearance rates. We used one-way ANOVA to compare associations between IC50s and the presence (+) or absence (−) of the SNP or microindel type. Chi-square analysis was used to compare associations between high (<36-h) or low (>90-h) parasite clearance rates and the presence (+) or absence (−) of the SNP or microindel type. *, P < 0.05 (significant findings are also highlighted in gray, for additional emphasis. #, the number of samples bearing each genotype. Results represent only the analysis for genotypes with allele frequencies of >8%.

Tables

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  • TABLE 1

    Membrane-spanning domains and transmembrane predictions for PfMRP2

    MSDTMPredicted TM domaina (aa span) based on:
    Previously published (13)OCTOPUSTMHMMO/T merged
    MSD11133–155133–157132–155134–155
    2180–202178–199180–203180–199
    3402–424401–422396–418401–418
    4434–456425–449428–454428–448
    5517–539511–531511–533512–531
    6554–575544–564548–565551–562
    —787–807——
    MSD27—1397–14191398–14261400–1417
    81430–14521445–14721446–14711448–1470
    1473–1495—1485–1506—
    91510–15321524–15451526–15461528–1545
    101553–15701547–15641547–15651547–1564
    111574–15931629–16581629–16511631–1651
    121654–16761667–16891671–16931671–1689
    • ↵a The TM segments shown are those reported from a previous study (13) or predicted in this study by using the OCTOPUS and TMHMM software. To obtain a reliable model, we supported the information for the TM segments obtained by merging the OCTOPUS/TMHMM probabilities (i.e., data in the O/T merged column). TM domain amino acid ranges shown in bold had the greatest differences from the data obtained from reference 13 or via analysis using the OCTOPUS and TMHMM software programs. TM column represents the transmembrane number for the O/T merged model. Dashes (—) represent TM segments.

  • TABLE 2

    SNPs identified in Pfmrp2 by sequencing the Thai isolates

    Chromosome positionaNucleotide positionNucleotide changeAmino acid positionAmino acid changeFrequency (proportion)Location
    1198644561T → A187Synonymous0.02 (1/46)TM2
    1198610*#595C → G199L → V1.00 (46/46)TM2
    1198321884C → G295T → R0.02 (1/46)loop
    1198275930G → T310L → F0.02 (1/46)loop
    1198224981C → T327Synonymous0.02 (1/46)loop
    1197428*§1777A → G593N → D0.07 (3/46)NBD1
    1197341*1864A → G622N → D0.22 (10/46)NBD1
    1197064*§#2141A → T714K → I1.00 (46/46)NBD1
    1196808*§2397C → T799Synonymous0.39 (16/41)NBD1
    1195791*§3414T → C1138Synonymous0.20 (9/44)NBD1
    1194626*#4579T → A1527S → T1.00 (46/46)TM9
    1194614*#4591C → A1531L → I1.00 (46/46)TM9
    11940935112T → C1704Synonymous0.02 (1/46)NBD2
    11939545251A → T1751N → Y0.09 (3/34)NBD2
    1193947§5258T → C1753F → S0.07 (3/46)NBD2
    11938825323A → G1775I → V0.14 (5/36)NBD2
    11938615344A → T1782M → L0.02 (1/46)NBD2
    11938205385A → T1795Synonymous0.08 (3/37)NBD2
    • ↵a Symbols: *, SNP previously registered with PlasmoDB; §, SNP previously found by deep sequencing of 227 samples from Africa, Asia, and Oceania (30); #, SNP previously described in reference 31.

Additional Files

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    Files in this Data Supplement:

    • Supplemental file 1 -

      Supplemental Figure S1: transmembrane probability of PfMRP2 2D structure. Table S1: oligonucleotide primer sequences.

      PDF, 137K

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Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response
Maria Isabel Veiga, Nuno S. Osório, Pedro Eduardo Ferreira, Oscar Franzén, Sabina Dahlstrom, J. Koji Lum, Francois Nosten, José Pedro Gil
Antimicrobial Agents and Chemotherapy Nov 2014, 58 (12) 7390-7397; DOI: 10.1128/AAC.03337-14

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Complex Polymorphisms in the Plasmodium falciparum Multidrug Resistance Protein 2 Gene and Its Contribution to Antimalarial Response
Maria Isabel Veiga, Nuno S. Osório, Pedro Eduardo Ferreira, Oscar Franzén, Sabina Dahlstrom, J. Koji Lum, Francois Nosten, José Pedro Gil
Antimicrobial Agents and Chemotherapy Nov 2014, 58 (12) 7390-7397; DOI: 10.1128/AAC.03337-14
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