BACKGROUND: In this post-hoc analysis, we determined the influence of single nucleotide polymorphisms in host candidate immune genes on the outcome of drug resistant malaria in Cameroon. METHODS: Human DNA from 760 patients from a previous clinical trial was subjected to mass spectrometry-based single nucleotide polymorphism (SNP) genotyping. Allele frequencies of candidate immune genes were calculated for 62 SNPs on 17 human chromosomes for their possible involvement in clearance of drug-resistant parasites with the triple mutations of pfcrt76T, pfmdr86Y, and pfmdr1246Y (TY) and pfdhfr51I, pfdhfr59R, pfdhfr108N, and pfdhps437G (IRNG) which were determined by dotblot or PCR-restriction analysis. Differences in SNP frequencies and association analysis were carried out by comparing Chi-square odds ratios (ORs) and stratified by Mantel-Haenzel statistics. An adjusted P value (OR) <0·0008 was considered significant. RESULTS: Post-treatment drug failure rates were amodiaquine (36·4%); sulpadoxine/pyrimethamine-amodiaquine combination (15·4%); and sulphadoxine/pyrimethamine (18·1%). SNPs in IL22, IL-4R1, and CD36 appeared to have been associated with clearance of resistant parasites [p = 0·017, OR (C allele):1·44, 95% CI (OR): 1·06-1·95]; [P = 0·014, OR = 1·31, 95% CI (OR): 1·07-1·83]; [P = 5·78×10(-5), OR = 0·27, 95%CI (OR): 0·13-0·54], respectively, with high fever (>39°C for 48 hours) [IL-22, P = 0·01, OR = 1·5, 95% CI (OR): 1·8-2·1] and also in high frequency among the Fulani participants [P = 0·006, OR = 1·83, 95% CI (OR): 1·11-3·08)]. The CD36-1264 null allele was completely absent in the northern population. CONCLUSION: Independent association of SNPs in IL22 and IL-4 with clearance of amodiaquine- and sulphadoxine/pyrimethamine-resistant parasites did not reach statistical significance, but may suggest that not all drug-resistant mutants are adversely affected by the same immune-mediated mechanisms of clearance.
RCT Entities:
BACKGROUND: In this post-hoc analysis, we determined the influence of single nucleotide polymorphisms in host candidate immune genes on the outcome of drug resistant malaria in Cameroon. METHODS:Human DNA from 760 patients from a previous clinical trial was subjected to mass spectrometry-based single nucleotide polymorphism (SNP) genotyping. Allele frequencies of candidate immune genes were calculated for 62 SNPs on 17 human chromosomes for their possible involvement in clearance of drug-resistant parasites with the triple mutations of pfcrt76T, pfmdr86Y, and pfmdr1246Y (TY) and pfdhfr51I, pfdhfr59R, pfdhfr108N, and pfdhps437G (IRNG) which were determined by dotblot or PCR-restriction analysis. Differences in SNP frequencies and association analysis were carried out by comparing Chi-square odds ratios (ORs) and stratified by Mantel-Haenzel statistics. An adjusted P value (OR) <0·0008 was considered significant. RESULTS: Post-treatment drug failure rates were amodiaquine (36·4%); sulpadoxine/pyrimethamine-amodiaquine combination (15·4%); and sulphadoxine/pyrimethamine (18·1%). SNPs in IL22, IL-4R1, and CD36 appeared to have been associated with clearance of resistant parasites [p = 0·017, OR (C allele):1·44, 95% CI (OR): 1·06-1·95]; [P = 0·014, OR = 1·31, 95% CI (OR): 1·07-1·83]; [P = 5·78×10(-5), OR = 0·27, 95%CI (OR): 0·13-0·54], respectively, with high fever (>39°C for 48 hours) [IL-22, P = 0·01, OR = 1·5, 95% CI (OR): 1·8-2·1] and also in high frequency among the Fulani participants [P = 0·006, OR = 1·83, 95% CI (OR): 1·11-3·08)]. The CD36-1264 null allele was completely absent in the northern population. CONCLUSION: Independent association of SNPs in IL22 and IL-4 with clearance of amodiaquine- and sulphadoxine/pyrimethamine-resistant parasites did not reach statistical significance, but may suggest that not all drug-resistant mutants are adversely affected by the same immune-mediated mechanisms of clearance.
Authors: T J Aitman; L D Cooper; P J Norsworthy; F N Wahid; J K Gray; B R Curtis; P M McKeigue; D Kwiatkowski; B M Greenwood; R W Snow; A V Hill; J Scott Journal: Nature Date: 2000-06-29 Impact factor: 49.962
Authors: D Modiano; G Luoni; B S Sirima; A Lanfrancotti; V Petrarca; F Cruciani; J Simporé; B M Ciminelli; E Foglietta; P Grisanti; I Bianco; G Modiano; M Coluzzi Journal: Trans R Soc Trop Med Hyg Date: 2001 Mar-Apr Impact factor: 2.184
Authors: Michael Alifrangis; Sonja Enosse; Insaf F Khalil; Donath S Tarimo; Martha M Lemnge; Richardo Thompson; Ib C Bygbjerg; Anita M Rønn Journal: Am J Trop Med Hyg Date: 2003-12 Impact factor: 2.345
Authors: Dianne J Terlouw; Michael A Aidoo; Venkatachalam Udhayakumar; Margarette S Kolczak; Aggrey J Oloo; Piet A Kager; Altaf A Lal; Bernard L Nahlen; Feiko O ter Kuile Journal: J Infect Dis Date: 2002-11-05 Impact factor: 5.226
Authors: M H Xie; S Aggarwal; W H Ho; J Foster; Z Zhang; J Stinson; W I Wood; A D Goddard; A L Gurney Journal: J Biol Chem Date: 2000-10-06 Impact factor: 5.157
Authors: Denise P Mawili-Mboumba; Steffen Borrmann; David R Cavanagh; Jana S McBride; Pierre-Blaise Matsiegui; Michel A Missinou; Peter G Kremsner; Francine Ntoumi Journal: J Infect Dis Date: 2003-03-13 Impact factor: 5.226
Authors: G Luoni; F Verra; B Arcà; B S Sirima; M Troye-Blomberg; M Coluzzi; D Kwiatkowski; D Modiano Journal: Genes Immun Date: 2001-11 Impact factor: 2.676
Authors: Abdoulaye A Djimdé; Ogobara K Doumbo; Ousmane Traore; Ando B Guindo; Kassoum Kayentao; Yacouba Diourte; Safiatou Niare-Doumbo; Drissa Coulibaly; Abdoulaye K Kone; Yacouba Cissoko; Mamadou Tekete; Bakary Fofana; Alassane Dicko; Dapa A Diallo; Thomas E Wellems; Dominic Kwiatkowski; Christopher V Plowe Journal: Am J Trop Med Hyg Date: 2003-11 Impact factor: 2.345
Authors: Benedicta A Mensah; Ozkan Aydemir; James L Myers-Hansen; Millicent Opoku; Nicholas J Hathaway; Patrick W Marsh; Francis Anto; Jeffrey Bailey; Benjamin Abuaku; Anita Ghansah Journal: Antimicrob Agents Chemother Date: 2020-03-24 Impact factor: 5.191
Authors: Pavitra N Rao; Swapna Uplekar; Sriti Kayal; Prashant K Mallick; Nabamita Bandyopadhyay; Sonal Kale; Om P Singh; Akshaya Mohanty; Sanjib Mohanty; Samuel C Wassmer; Jane M Carlton Journal: J Clin Microbiol Date: 2016-03-23 Impact factor: 5.948