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Association of common single-nucleotide polymorphisms in innate immune genes with differences in TLR-induced cytokine production in neonates

Genes & Immunity volume 14, pages 199–211 (2013)Cite this article

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Abstract

Significant variability in cytokine and chemokine expression after Toll-like receptor (TLR) stimulation has been observed between individuals. In this study, we determined the immunophenotypic variation in a cohort of 152 neonates associated with specific single-nucleotide polymorphisms (SNPs). We identified 23 SNPs in 12 genes of the innate immune system to be significantly associated with differential cytokine and chemokine production. SNPs in three gene families, namely STAT, IRF and SYK, accounted for most associations. These gene families are important signaling components of the innate anti-viral response. A potentially damaging non-synonymous SNP in the TLR3 gene (rs3775291) associated with significant differences in expression of interferon-γ after stimulation with the synthetic TLR3 ligand, poly (I:C). Additionally, a general increase in cytokine production was observed in subjects of Asian descent. This observation could be associated with differences in SNP genotype distribution between racial groups in our cohort. Taken together, our data suggest that particular aspects of the newborn innate response to TLR stimulation are closely associated with genetic variation. These findings provide the basis for detailed molecular dissection of cause–effect relationships between genotype and immune responses, and may account for inter-individual differences in response to vaccination and risk for infection and autoimmune disease.

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Acknowledgements

This work was supported in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health Grant N01 AI50023 and the AllerGen NCE Grants 07-A1A and 07-B2B. PC is funded by a graduate studentship from the Public Health Agency of Canada/CIHR Influenza Research Network. LG is a recipient of a Frederick Banting and Charles Best Canada Graduate Scholarship from the CIHR. NPC is a recipient of an NSERC graduate studentship. Trainees in the Kollmann lab are supported in part by an educational grant from GlaxoSmithKline Inc. SET is supported in part by the Aubrey J Tingle Professorship in Pediatric Immunology and a Clinical Research Scholar Award from the Michael Smith Foundation for Health Research. TRK is supported in part by a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund, and by a Michael Smith Foundation for Health Research Career Investigator Award. We would like to thank Jian Ruan, Sarah Kam, Helena Lee and the staff at the Genome Quebec Innovation Centre for their technical assistance, Kevin Ho for his assistance with the figures, and Colin Ross for helpful discussion. We would also like to thank Drs Christopher B. Wilson and Adeline M Hajjar of the University of Washington Medical Center who were the principal investigators of the N01 AI50023 grant. TRK has received research grants from the Canadian Institutes of Health Research, the US National Institute of Allergy and Infectious Diseases, GlaxoSmithKline, Merck, Advaxis, Allergen NCE, Child and Family Research Institute, SickKids Foundation and the Burroughs Wellcome Fund.

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Author notes

  1. P Cho and L Gelinas: These authors contributed equally to this work.

  2. E S Fortuno and T R Kollmann: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada

    P Cho, L Gelinas, N P Corbett & T R Kollmann

  2. NCE CECR PROOF Centre of Excellence, Vancouver, British Columbia, Canada

    S J Tebbutt

  3. Division of Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    S J Tebbutt

  4. UBC James Hogg Research Centre and Institute for HEART+LUNG Health, Vancouver, British Columbia, Canada

    S J Tebbutt

  5. Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada

    S E Turvey, E S Fortuno III & T R Kollmann

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  1. P Cho
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  2. L Gelinas
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Correspondence to T R Kollmann.

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Competing interests

TRK is an investigator for clinical trials conducted by the University of British Columbia’s Vaccine Evaluation Center sponsored by governmental sources (for example, CIHR and NIH) and vaccine manufacturers (Merck, Novartis Vaccines, GlaxoSmithKline, Sanofi-Pasteur and Wyeth Vaccines), but has not received any personal payment from them. The remaining authors declare no conflict of interest.

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Cho, P., Gelinas, L., Corbett, N. et al. Association of common single-nucleotide polymorphisms in innate immune genes with differences in TLR-induced cytokine production in neonates. Genes Immun 14, 199–211 (2013). https://doi.org/10.1038/gene.2013.5

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