Journal
GENES AND IMMUNITY
Volume 14, Issue 1, Pages 52-57Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2012.53
Keywords
TLR; polymorphism; genomics; innate immunity
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Funding
- National Heart, Lung, and Blood Institute [R01 HL089807-01]
- National Institute of Allergy and Infectious Diseases [U54 AI057141]
- National Institute of Aging Longevity Consortium [U19AG023122]
- NIH NHLBI [T32 HL 7287-33]
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Toll-like receptor (TLR)-mediated innate immune responses are important in early host defense. Using a candidate gene approach, we previously identified genetic variation within TLR1 that is associated with hyper-responsiveness to a TLR1/2 agonist in vitro and with death and organ dysfunction in patients with sepsis. Here we report a genome-wide association study (GWAS) designed to identify genetic loci controlling whole blood cytokine responses to the TLR1/2 lipopeptide agonist, Pam(3)CSK(4) (N-palmitoyl-S-dipalmitoylglyceryl Cys-Ser-(Lys)(4)) ex vivo. We identified a very strong association (P < 1 x 10(-27)) between genetic variation within the TLR10/1/6 locus on chromosome 4, and Pam(3)CSK(4)-induced cytokine responses. This was the predominant association explaining over 35% of the population variance for this phenotype. Notably, strong associations were observed within TLR10, suggesting that genetic variation in TLR10 may influence bacterial lipoprotein-induced responses. These findings establish the TLR10/1/6 locus as the dominant common genetic factor controlling interindividual variability in Pam(3)CSK(4)-induced whole blood responses in the healthy population. Genes and Immunity (2013) 14, 52-57; doi: 10.1038/gene.2012.53; published online 15 November 2012
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