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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.Background: Multiple environmental and genetic factors play a role in the pathogenesis of atopic eczema (AE). We aimed to investigate gene–environment interactions (G × E) to improve understanding of the pathophysiology. Methods: We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modeling to independently assess findings. Results: The discovery analysis (including 25,339 individuals) showed suggestive evidence for interaction (p < 0.05) between seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total. In the replication analysis (254,532 individuals) dog exposure × rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction = 0.91 [0.83–0.99] p = 0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction = 0.84 [0.75–0.94] p = 0.003), but replication analysis was under-powered (ORinteraction = 1.09 [0.82–1.46]). rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. Conclusion: Interaction analysis and functional assessment provide preliminary evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G × E studied here implies only weak effects are likely to occur.
Author(s): Standl M, Budu-Aggrey A, Johnston LJ, Elias MS, Arshad SH, Bager P, Bataille V, Blakeway H, Bonnelykke K, Boomsma D, Brumpton BM, Bustamante Pineda M, Campbell A, Curtin JA, Eliasen A, Fadista JPS, Feenstra B, Gerner T, Medina-Gomez C, Grosche S, Gutzkow KB, Halling A-S, Hayward C, Henderson J, Herrera-Luis E, Holloway JW, Hottenga J, O'B Hourihane J, Hu C, Hveem K, Irizar A, Jacquemi B, Jessen L, Kress S, Kurukulaaratchy RJ, Lau S, Llop S, Loset M, Marenholz I, Mason D, McCartney DL, Melbye M, Melen E, Minica C, Murray CS, Nijsten T, Pardo LM, Pasmans S, Pennell CE, Rinnov MR, Santorelli G, Schikowski T, Sheehan D, Simpson A, Soderhall C, Thomas LF, Thyssen JP, Torrent M, van Beijsterveldt T, Visconti A, Vonk JM, Wang CA, Xu C-J, Ziyab AH, Custovic A, Di Meglio P, Duijts L, Flohr C, Irvine AD, Koppelman GH, Lee Y-A, Reynolds NJ, Smith C, Langan SM, Paternoster L, Brown SJ
Publication type: Article
Publication status: Published
Journal: Allergy: European Journal of Allergy and Clinical Immunology
Year: 2025
Volume: 80
Issue: 8
Pages: 2201-2212
Print publication date: 01/08/2025
Online publication date: 04/06/2025
Acceptance date: 11/05/2025
Date deposited: 26/06/2025
ISSN (print): 0105-4538
ISSN (electronic): 1398-9995
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1111/all.16605
DOI: 10.1111/all.16605
Data Access Statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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