title: Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses.
abstract: 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 × 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, USA. cmikacen@uw.edu
authors.forename: C
authors.initials: C
authors.lastname: Mikacenic
authors.forename: A P
authors.initials: AP
authors.lastname: Reiner
authors.forename: T D
authors.initials: TD
authors.lastname: Holden
authors.forename: D A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: M M
authors.initials: MM
authors.lastname: Wurfel
mesh_terms: D000328:Adult; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D016207:Cytokines / Q000097:blood* / Q000235:genetics / Q000276:immunology; D005260:Female; D005799:Genes, Dominant; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D055666:Lipopeptides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology*; D051194:Toll-Like Receptor 1 / Q000819:agonists / Q000235:genetics; D051201:Toll-Like Receptor 10 / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000819:agonists; D051216:Toll-Like Receptor 6 / Q000235:genetics; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics*
chemical_list: D016207:Cytokines; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors