title: Global sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: implications for the performance of malaria rapid diagnostic tests.
abstract: BACKGROUND
  Accurate diagnosis is essential for prompt and appropriate treatment of malaria. While rapid diagnostic tests (RDTs) offer great potential to improve malaria diagnosis, the sensitivity of RDTs has been reported to be highly variable. One possible factor contributing to variable test performance is the diversity of parasite antigens. This is of particular concern for Plasmodium falciparum histidine-rich protein 2 (PfHRP2)-detecting RDTs since PfHRP2 has been reported to be highly variable in isolates of the Asia-Pacific region.
  
  
  METHODS
  The pfhrp2 exon 2 fragment from 458 isolates of P. falciparum collected from 38 countries was amplified and sequenced. For a subset of 80 isolates, the exon 2 fragment of histidine-rich protein 3 (pfhrp3) was also amplified and sequenced. DNA sequence and statistical analysis of the variation observed in these genes was conducted. The potential impact of the pfhrp2 variation on RDT detection rates was examined by analysing the relationship between sequence characteristics of this gene and the results of the WHO product testing of malaria RDTs: Round 1 (2008), for 34 PfHRP2-detecting RDTs.
  
  
  RESULTS
  Sequence analysis revealed extensive variations in the number and arrangement of various repeats encoded by the genes in parasite populations world-wide. However, no statistically robust correlation between gene structure and RDT detection rate for P. falciparum parasites at 200 parasites per microlitre was identified.
  
  
  CONCLUSIONS
  The results suggest that despite extreme sequence variation, diversity of PfHRP2 does not appear to be a major cause of RDT sensitivity variation.
authors.affiliation: Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia. qin.cheng@defence.gov.au.
authors.forename: Joanne
authors.initials: J
authors.lastname: Baker
authors.forename: Mei-Fong
authors.initials: MF
authors.lastname: Ho
authors.forename: Anita
authors.initials: A
authors.lastname: Pelecanos
authors.forename: Michelle
authors.initials: M
authors.lastname: Gatton
authors.forename: Nanhua
authors.initials: N
authors.lastname: Chen
authors.forename: Salim
authors.initials: S
authors.lastname: Abdullah
authors.forename: Audrey
authors.initials: A
authors.lastname: Albertini
authors.forename: Frederic
authors.initials: F
authors.lastname: Ariey
authors.forename: John
authors.initials: J
authors.lastname: Barnwell
authors.forename: David
authors.initials: D
authors.lastname: Bell
authors.forename: Jane
authors.initials: J
authors.lastname: Cunningham
authors.forename: Djibrine
authors.initials: D
authors.lastname: Djalle
authors.forename: Diego F
authors.initials: DF
authors.lastname: Echeverry
authors.forename: Dionicia
authors.initials: D
authors.lastname: Gamboa
authors.forename: Jeffery
authors.initials: J
authors.lastname: Hii
authors.forename: Myat Phone
authors.initials: MP
authors.lastname: Kyaw
authors.forename: Jennifer
authors.initials: J
authors.lastname: Luchavez
authors.forename: Christopher
authors.initials: C
authors.lastname: Membi
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
authors.forename: Claribel
authors.initials: C
authors.lastname: Murillo
authors.forename: Sina
authors.initials: S
authors.lastname: Nhem
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.forename: Pamela
authors.initials: P
authors.lastname: Onyor
authors.forename: Wellington
authors.initials: W
authors.lastname: Oyibo
authors.forename: Shan Qing
authors.initials: SQ
authors.lastname: Wang
authors.forename: James
authors.initials: J
authors.lastname: McCarthy
authors.forename: Qin
authors.initials: Q
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology; D016054:DNA, Protozoan / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007118:Immunoassay / Q000379:methods* / Q000592:standards; D016778:Malaria, Falciparum / Q000175:diagnosis* / Q000235:genetics / Q000469:parasitology; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification*; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology; D011933:Reagent Kits, Diagnostic; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA
chemical_list: D000953:Antigens, Protozoan; D016054:DNA, Protozoan; C514457:HRP-2 antigen, Plasmodium falciparum; D015800:Protozoan Proteins; D011933:Reagent Kits, Diagnostic
references.citation: Am J Trop Med Hyg. 2008 Feb;78(2):217-21
references.pmid: 18256418
references.citation: Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):119-27
references.pmid: 18165483
references.citation: Am J Trop Med Hyg. 2006 Dec;75(6):1209-15
references.pmid: 17172395
references.citation: Malar J. 2008 Jul 03;7:118
references.pmid: 18598344
references.citation: Ethiop Med J. 1999 Jul;37(3):173-9
references.pmid: 11957314
references.citation: J Infect Dis. 2005 Sep 1;192(5):870-7
references.pmid: 16088837
references.citation: Exp Parasitol. 1988 Aug;66(2):143-70
references.pmid: 3294023
references.citation: Mol Biochem Parasitol. 2007 Sep;155(1):33-44
references.pmid: 17599553
references.citation: Mol Biochem Parasitol. 1989 Jun 15;35(2):149-60
references.pmid: 2671720
references.citation: PLoS One. 2010 Jan 25;5(1):e8091
references.pmid: 20111602
references.citation: FEBS Lett. 2003 Oct 9;553(1-2):135-40
references.pmid: 14550561
references.citation: Science. 2002 Oct 4;298(5591):216-8
references.pmid: 12364807
references.citation: P N G Med J. 1986 Mar;29(1):87-93
references.pmid: 3463018
references.citation: Parasitology. 1987 Oct;95 ( Pt 2):209-27
references.pmid: 3320887
references.citation: Trends Parasitol. 2001 Jul;17(7):307-9
references.pmid: 11423356
references.citation: Biotechnol Lett. 2004 Jul;26(13):1051-5
references.pmid: 15218378
references.citation: Ann Trop Med Parasitol. 2005 Sep;99(6):553-62
references.pmid: 16156968
references.citation: Science. 1976 Feb 13;191(4227):528-35
references.pmid: 1251186
references.citation: Biochemistry. 1999 Dec 21;38(51):16916-24
references.pmid: 10606526
references.citation: Turkiye Parazitol Derg. 2005;29(3):149-53
references.pmid: 17160810
references.citation: Annu Rev Microbiol. 1987;41:181-208
references.pmid: 3318667
references.citation: Int J Biochem. 1988;20(5):471-7
references.pmid: 3286310
references.citation: Proc Natl Acad Sci U S A. 1987 Nov;84(21):7672-6
references.pmid: 3313401
references.citation: Science. 1996 Jan 12;271(5246):219-22
references.pmid: 8539625
references.citation: Lancet. 2004 Nov 20-26;364(9448):1896-8
references.pmid: 15555670
references.citation: Parasitology. 2005 Dec;131(Pt 6):727-35
references.pmid: 16336726
references.citation: J Clin Microbiol. 2006 Aug;44(8):2773-8
references.pmid: 16891491
references.citation: EMBO J. 2002 Feb 15;21(4):815-24
references.pmid: 11847128
references.citation: Proc Natl Acad Sci U S A. 1986 Aug;83(16):6065-9
references.pmid: 3016741
references.citation: J Clin Microbiol. 2006 Dec;44(12):4547-9
references.pmid: 17021060
references.citation: Mol Biol Evol. 1987 May;4(3):203-21
references.pmid: 3328815
references.citation: Nucleic Acids Res. 1992 Apr 11;20(7):1491-6
references.pmid: 1579440
references.citation: J Mol Evol. 2004 Oct;59(4):528-35
references.pmid: 15638464
references.citation: Trans R Soc Trop Med Hyg. 1999 Sep-Oct;93(5):519-20
references.pmid: 10696409
references.citation: Cell. 1987 Jun 5;49(5):633-42
references.pmid: 2884039
references.citation: Cell. 1988 Dec 2;55(5):869-74
references.pmid: 3056622
references.citation: Exp Parasitol. 2000 Nov;96(3):139-46
references.pmid: 11162364
references.citation: PLoS Med. 2005 Aug;2(8):e204
references.pmid: 16104831
references.citation: Mol Biochem Parasitol. 1988 Mar;28(2):85-94
references.pmid: 3285206
references.citation: Mol Biochem Parasitol. 2003 May;128(2):157-66
references.pmid: 12742582
references.citation: J Cell Biol. 1986 Oct;103(4):1269-77
references.pmid: 3533951
references.citation: Acta Trop. 2000 May 31;75(3):349-59
references.pmid: 10838219