Original Paper

Parasitology Research

, Volume 100, Issue 1, pp 141-148

First online:

Linkage disequilibrium between two distinct loci in chromosomes 5 and 7 of Plasmodium falciparum and in vivo chloroquine resistance in Southwest Nigeria

  • C. T. HappiAffiliated withMalaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of IbadanDepartment of Immunology and Infectious Diseases, Harvard School of Public Health Email author 
  • , G. O. GbotoshoAffiliated withMalaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
  • , O. A. FolarinAffiliated withMalaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
  • , A. SowunmiAffiliated withMalaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
  • , O. M. BolajiAffiliated withMalaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
  • , B. A. FateyeAffiliated withMalaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan
  • , D. E. KyleAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , W. MilhousAffiliated withDivision of Experimental Therapeutics, Walter Reed Army Institute of Research
  • , D. F. WirthAffiliated withDepartment of Immunology and Infectious Diseases, Harvard School of Public Health
    • , A. M. J. OduolaAffiliated withSpecial Programme for Research and Training in Tropical Diseases (WHO/TDR)

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Abstract

Chloroquine (CQ) resistance in Plasmodium falciparum is associated with polymorphisms in loci on pfcrt and pfmdr1 genes. In this study, we determined the association and linkage disequilibrium between in vivo CQ resistance and P. falciparum polymorphisms in pfcrt gene at codon 76 and pfmdr1 gene at codon 86 in isolates obtained from 111 children with acute uncomplicated falciparum malaria in Nigeria. Patients were treated with standard dosage of CQ and followed up for 28 days. Filter paper samples were collected at enrollment and during follow-up for parasites genotypes and identification of pfcrt and pfmdr1 mutations. Association and linkage disequilibrium between mutant pfcrtT76 and pfmdr1Y86 alleles in pretreatment isolates of P. falciparum was determined. Fifty-five out of the 111 patients (49.5%) failed treatment. Single mutant pfcrtT76 or pfmdr1Y86 alleles were found in 55 out of 111 P. falciparum isolates screened at enrollment. Of these 55 isolates, the mutant pfcrtT76 and pfmdr1Y86 alleles were found in 84%. Both mutant pfcrtT76 (p=0.0196) and pfmdr1Y86 (p=0.000042) alleles were associated with in vivo CQ resistance. In addition, the mutant pfcrtT76 (p=0.047) and pfmdr1Y86 (p=0.006) alleles were significantly selected by CQ in patients who failed treatment. Association analysis between paired single alleles at pfcrt and pfmdr1 loci showed a significant association (p=0.0349 and χ 2=4.45) between the pfcrt T76 allele on chromosome 7 and the pfmdr1Y86 allele on chromosome 5 and that these two mutant alleles were in linkage disequilibrium (p=0.000, D′=0.64, and r 2=0.28). Considering the high level of CQ resistance and drug use in the study area, the observed linkage disequilibrium between the mutant pfcrtT76 and pfmdr1Y86 alleles is maintained epistatically through directional CQ selective pressure.