Host candidate gene polymorphisms and associated clearance of P. falciparum amodiaquine and fansidar resistance mutants in children less than 5 years in Cameroon.
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.


CONCLUSIONS
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.
Innocent Mbulli
IM
Ali
Marie-Solange Bebandue
MS
Evehe
Palmer Masumbe
PM
Netongo
Barbara
B
Atogho-Tiedeu
Mbuh
M
Akindeh-Nji
Honore
H
Ngora
Irenee Kamogne
IK
Domkam
Mahamadou
M
Diakite
Khan
K
Baldip
Lisa
L
Ranford-Cartwright
Patrice Nsangou
PN
Mimche
Tracey
T
Lamb
Wilfred Fon
WF
Mbacham
D000655:Amodiaquine / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D002163:Cameroon; D002675:Child, Preschool; D004338:Drug Combinations; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015847:Interleukin-4 / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology* / Q000469:parasitology; D008297:Male; D010963:Plasmodium falciparum / Q000187:drug effects / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011739:Pyrimethamine / Q000494:pharmacology; D013413:Sulfadoxine / Q000494:pharmacology; D000097043:Interleukin-22
D000655:Amodiaquine; D000962:Antimalarials; D004338:Drug Combinations; D015847:Interleukin-4; D007378:Interleukins; D011739:Pyrimethamine; D013413:Sulfadoxine; D000097043:Interleukin-22; C508598:IL4 protein, human; C001205:fanasil, pyrimethamine drug combination
Amodiaquine,; Drug resistance markers,; Fever clearance,; Immune response; Interleukin-22,; Parasite clearance,; Sulphadoxine/pyrimethamine,