Immune Responsiveness to LPS Determines Risk of Childhood Wheeze and Asthma in 17q21 Risk Allele Carriers

Sabina Illi* (Corresponding Author), Martin Depner, Petra Ina Pfefferle, Harald Renz, Caroline Roduit, Diana Hazard Taft, Karen M. Kalanetra, David A. Mills, Freda M. Farquharson, Petra Louis, Elisabeth Schmausser-Hechfellner, Amandine Divaret-Chauveau, Roger Lauener, Anne M. Karvonen, Juha Pekkanen, Pirkka V. Kirjavainen, Marjut Roponen, Josef Riedler, Michael Kabesch, Bianca SchaubErika von Mutius, and the PASTURE Study Group

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


Rationale: In murine models, microbial exposures induce protection from experimental allergic asthma through innate immunity. Objectives: Our aim was to assess the association of early life innate immunity with the development of asthma in children at risk. Methods: In the PASTURE farm birth cohort, innate T-helper cell type 2 (Th2), Th1, and Th17 cytokine expression at age 1 year was measured after stimulation of peripheral blood mononuclear cells with LPS in n = 445 children. Children at risk of asthma were defined based on single-nucleotide polymorphisms at the 17q21 asthma gene locus. Specifically, we used the SNP rs7216389 in the GSDMB gene. Wheeze in the first year of life was assessed by weekly diaries and asthma by questionnaire at age 6 years. Measurements and Main Results: Not all cytokines were detectable in all children after LPS stimulation. When classifying detectability of cytokines by latent class analysis, carrying the 17q21 risk allele rs7216389 was associated with risk of wheeze only in the class with the lowest level of LPS-induced activation: odds ratio (OR), 1.89; 95% confidence interval [CI], 1.13-3.16; P = 0.015. In contrast, in children with high cytokine activation after LPS stimulation, no association of the 17q21 risk allele with wheeze (OR, 0.63; 95% CI, 0.29-1.40; P = 0.258, P = 0.034 for interaction) or school-age asthma was observed. In these children, consumption of unprocessed cow's milk was associated with higher cytokine activation (OR, 3.37; 95% CI, 1.56-7.30; P = 0.002), which was in part mediated by the gut microbiome. Conclusions: These findings suggest that within the 17q21 genotype, asthma risk can be mitigated by activated immune responses after innate stimulation, which is partly mediated by a gut-immune axis.

Original languageEnglish
Pages (from-to)641-650
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Issue number6
Early online date17 Dec 2021
Publication statusPublished - 17 Dec 2021


  • 17q21 genotype
  • farm environment
  • gut microbiome
  • innate immune response in children
  • unprocessed cow’s milk


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