Polymorphisms in TLR4 and TLR2 genes, cytokine production and survival in rural Ghana.
Toll-like receptors (TLRs) are involved in the induction of an adequate immune response on infection. We hypothesized that genetic variation in TLR4 and TLR2 genes could influence this response and lead to variability in cytokine production and survival. We tested this hypothesis in 4292 participants who were followed up for all-cause mortality for 6 years and live under adverse environmental conditions in the Upper-East region of Ghana, where malaria is endemic. In 605 participants, tumor necrosis factor-alpha and interleukin-10 (IL10) production, after stimulation with lipopolysaccharide and zymosan, was measured. In addition, 34 single-nucleotide polymorphisms (SNPs) in TLR4 and 12 SNPs in TLR2 were genotyped and tested for association with cytokine production, malaria infection and mortality. In this comprehensive gene-wide approach, we identified novel SNPs in the TLR4 gene that influence cytokine production. From the analyzed SNPs, rs7860896 associated the strongest with IL10 production (P=0.0005). None of the SNPs in this study associated with malaria or overall mortality risks. In conclusion, we demonstrate that genetic variation within the TLR4 gene influences cytokine production capacity, but in an endemic area does not influence the susceptibility to malaria infection or mortality.
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
Linda
L
May
David
D
van Bodegom
Marijke
M
Frölich
Lisette
L
van Lieshout
P Eline
PE
Slagboom
Rudi G J
RG
Westendorp
Maris
M
Kuningas
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D005869:Ghana; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000235:genetics / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015996:Survival Rate; D051195:Toll-Like Receptor 2 / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055815:Young Adult
D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10