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Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses

Genes & Immunity volume 14, pages 52–57 (2013)Cite this article

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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, Pam3CSK4 (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 Pam3CSK4-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 Pam3CSK4-induced whole blood responses in the healthy population.

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Acknowledgements

This work was supported by the National Heart, Lung, and Blood Institute Grant R01 HL089807-01 (to MMW), National Institute of Allergy and Infectious Diseases Grant U54 AI057141 (to MMW), National Institute of Aging Longevity Consortium Grant U19AG023122 (to APR), and the NIH NHLBI training grant T32 HL 7287-33 (CM).

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA

    C Mikacenic, T D Holden & M M Wurfel

  2. Department of Epidemiology, University of Washington, Seattle, WA, USA

    A P Reiner

  3. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    D A Nickerson

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  1. C Mikacenic
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Mikacenic, C., Reiner, A., Holden, T. et al. Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses. Genes Immun 14, 52–57 (2013). https://doi.org/10.1038/gene.2012.53

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