Variants in the toll-like receptor signaling pathway and clinical outcomes of malaria.
BACKGROUND
Malaria is one of the most significant infectious diseases in the world and is responsible for a large proportion of infant deaths. Toll-like receptors (TLRs), key components of innate immunity, are central to countering infection. Variants in the TLR-signaling pathway are associated with susceptibility to infectious diseases.


METHODS
We genotyped single nucleotide polymorphisms (SNPs) of the genes associated with the TLR-signaling pathway in patients with mild malaria and individuals with asymptomatic Plasmodium infections by means of polymerase chain reaction.


RESULTS
Genotype distributions for the TLR-1 I602S differed significantly between patients with mild malaria and persons with asymptomatic infection. The TLR-1 602S allele was associated with an odds ratio (OR) of 2.2 (P= .003; P(corrected)= .015) for malaria among patients with mild malaria due to any Plasmodium species and 2.1 (P= .015; P(corrected)= .75) among patients with mild malaria due to Plasmodium falciparum only. The TLR-6 S249P SNP showed an excess of homozygotes for the TLR-6 249P allele in asymptomatic persons, compared with patients with mild malaria due to any Plasmodium species (OR 2.1; 95% confidence interval [CI], 1.1- 4.2; P= .01; P(corrected)= .05), suggesting that the TLR-6 249S allele may be a risk factor for malaria (OR, 2.0; 95% CI, 1.1-3.7; P=0.01; P(corrected)= .05). The TLR-9 -1486C allele showed a strong association with high parasitemia (P< .001).


CONCLUSIONS
Our findings indicate that the TLR-1 and TLR-6 variants are significantly associated with mild malaria, whereas the TLR-9-1486C/T variants are associated with high parasitemia. These discoveries may bring additional understanding to the pathogenesis of malaria.
Leoratti
Fabiana M S
FM
Instituto de Medicina Tropical de São Paulo, University of São Paulo, São Paulo, Brazil.
Farias
Lilian
L
Alves
Fabiana P
FP
Suarez-Mútis
Martha C
MC
Coura
José R
JR
Kalil
Jorge
J
Camargo
Erney P
EP
Moraes
Sandra L
SL
Ramasawmy
Rajendranath
R
D000328:Adult; D000375:Aging; D000962:Antimalarials / Q000627:therapeutic use; D001938:Brazil; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D008297:Male; D016017:Odds Ratio; D018512:Parasitemia / Q000469:parasitology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
D000962:Antimalarials; D051193:Toll-Like Receptors