title: Host candidate gene polymorphisms and clearance of drug-resistant Plasmodium falciparum parasites.
abstract: BACKGROUND
  Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches.
  
  
  METHODS
  3721 samples from five African countries, which were known to contain genotypically drug resistant parasites, were analysed. These parasites were collected from patients who subsequently failed to clear their infection following drug treatment, as expected, but also from patients who successfully cleared their infections with drug-resistant parasites. 67 human polymorphisms (SNPs) on 17 chromosomes were analysed using Sequenom's mass spectrometry iPLEX gold platform, to identify regions of the human genome, which contribute to enhanced clearance of drug resistant parasites.
  
  
  RESULTS
  An analysis of all data from the five countries revealed significant associations between the phenotype of ability to clear drug-resistant Plasmodium falciparum infection and human immune response loci common to all populations. Overall, three SNPs showed a significant association with clearance of drug-resistant parasites with odds ratios of 0.76 for SNP rs2706384 (95% CI 0.71-0.92, P = 0.005), 0.66 for SNP rs1805015 (95% CI 0.45-0.97, P = 0.03), and 0.67 for SNP rs1128127 (95% CI 0.45-0.99, P = 0.05), after adjustment for possible confounding factors. The first two SNPs (rs2706384 and rs1805015) are within loci involved in pro-inflammatory (interferon-gamma) and anti-inflammatory (IL-4) cytokine responses. The third locus encodes a protein involved in the degradation of misfolded proteins within the endoplasmic reticulum, and its role, if any, in the clearance phenotype is unclear.
  
  
  CONCLUSIONS
  The study showed significant association of three loci in the human genome with the ability of parasite to clear drug-resistant P. falciparum in samples taken from five countries distributed across sub-Saharan Africa. Both SNP rs2706384 and SNP1805015 have previously been reported to be associated with risk of malaria infection in African populations. The loci are involved in the Th1/Th2 balance, and the association of SNPs within these genes suggests a key role for antibody in the clearance of drug-resistant parasites. It is possible that patients able to clear drug-resistant infections have an enhanced ability to control parasite growth.
authors.affiliation: Malaria Research and Training Centre, Faculty of Medicine, Pharmacy and Odontostomatology, University of Bamako, Mali. mdiakite@icermali.org
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakite
authors.forename: Eric A
authors.initials: EA
authors.lastname: Achidi
authors.forename: Olivia
authors.initials: O
authors.lastname: Achonduh
authors.forename: Rachel
authors.initials: R
authors.lastname: Craik
authors.forename: Abdoulaye A
authors.initials: AA
authors.lastname: Djimde
authors.forename: Marie-Solange B
authors.initials: MS
authors.lastname: Evehe
authors.forename: Angie
authors.initials: A
authors.lastname: Green
authors.forename: Christina
authors.initials: C
authors.lastname: Hubbart
authors.forename: Muntasir
authors.initials: M
authors.lastname: Ibrahim
authors.forename: Anna
authors.initials: A
authors.lastname: Jeffreys
authors.forename: Baldip K
authors.initials: BK
authors.lastname: Khan
authors.forename: Francis
authors.initials: F
authors.lastname: Kimani
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Wilfred F
authors.initials: WF
authors.lastname: Mbacham
authors.forename: Sabah Omar
authors.initials: SO
authors.lastname: Jezan
authors.forename: Jean Bosco
authors.initials: JB
authors.lastname: Ouedraogo
authors.forename: Kirk
authors.initials: K
authors.lastname: Rockett
authors.forename: Kate
authors.initials: K
authors.lastname: Rowlands
authors.forename: Nawal
authors.initials: N
authors.lastname: Tagelsir
authors.forename: Mamadou M
authors.initials: MM
authors.lastname: Tekete
authors.forename: Issaka
authors.initials: I
authors.lastname: Zongo
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Ranford-Cartwright
mesh_terms: D000293:Adolescent; D000349:Africa; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000276:immunology* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide
chemical_list: D000962:Antimalarials