Role of polymorphisms of toll-like receptor (TLR) 4, TLR9, toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A genes in malaria susceptibility and severity in Burundian children.
BACKGROUND
Malaria caused by Plasmodium falciparum is one of the leading causes of human morbidity and mortality from infectious diseases, predominantly in tropical and sub-tropical countries. As genetic variations in the toll-like receptors (TLRs)-signalling pathway have been associated with either susceptibility or resistance to several infectious and inflammatory diseases, the supposition is that single nucleotide polymorphisms (SNPs) of TLR2, TLR4, TLR9, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) and FCGR2A could modulate malaria susceptibility and severity.


METHODS
This study was planned to make a further contribution to solving the problem of the real role of the most common polymorphisms of TLR4, TLR9, TIRAP and FCGR2A genes in modulating the risk of malaria and disease severity in children from Burundi, Central Africa. All the paediatric patients aged six months to 10 years admitted to the hospital of Kiremba, Burundi, between February 2011 and September 2011, for fever and suspicion of acute malaria were screened for malaria parasitaemia by light microscopy of thick and thin blood smears. In children with malaria and in uninfected controls enrolled during the study period in the same hospital, blood samples were obtained on filter paper and TLR4 Asp299Gly rs4986790, TLR9 G1174A rs352139, T-1486 C rs187084 TLR9 T-1237 C rs5743836, TIRAP Ser180Leu rs8177374 and the FCGR2A His131Arg rs1801274 polymorphisms were studied using an ABI PRISM 7900 HT Fast Real-time instrument.


RESULTS
A total of 602 patients and 337 controls were enrolled. Among the malaria cases, 553 (91.9%) were considered as suffering from uncomplicated and 49 (8.1%) from severe malaria. TLR9 T1237C rs5743836CC was associated with an increased risk of developing malaria (p=0.03), although it was found with the same frequency in uncomplicated and severe malaria cases. No other differences were found in all alleles studied and in genotype frequencies between malaria cases and uninfected controls as well as between uncomplicated and severe malaria cases.


CONCLUSIONS
TLR9 T1237C seems to condition susceptibility to malaria in Burundian children but not its severity, whereas none of the assessed SNPs of TLR4, TIRAP and FCGR2A seem to influence susceptibility to malaria and disease severity in this population.
Pediatric Clinic 1, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122, Milan, Italy.
Susanna
S
Esposito
Claudio Giuseppe
CG
Molteni
Alberto
A
Zampiero
Elena
E
Baggi
Anna
A
Lavizzari
Margherita
M
Semino
Cristina
C
Daleno
Michela
M
Groppo
Alessia
A
Scala
Leonardo
L
Terranova
Monica
M
Miozzo
Claudio
C
Pelucchi
Nicola
N
Principi
D002063:Burundi; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000175:diagnosis / Q000235:genetics* / Q000469:parasitology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008853:Microscopy; D018512:Parasitemia / Q000175:diagnosis; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics
C445323:FCGR2A protein, human; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9