Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modellingin vitro
Authors: Standl Marie , Budu-Aggrey Ashley , Johnston Luke J , Elias Martina S , Arshad S Hasan , Bager Peter , Bataille Veronique , Blakeway Helena , Bonnelykke Klaus , Boomsma Dorret , Brumpton Ben M , Pineda Mariona Bustamante , Campbell Archie , Curtin John A , Eliasen Anders , Fadista João PS , Feenstra Bjarke , Gerner Trine , Gomez Carolina Medina , Grosche Sarah , Gutzkow Kristine B. , Halling Anne-Sofie , Hayward Caroline , Henderson John , Herrera-Luis Esther , Holloway John W , Hottenga Joukejan , Hourihane Jonathan O’B , Hu Chen , Hveem Kristian , Irizar Amaia , Jacquemi Benedicte , Jessen Leon , Kress Sara , Kurukulaaratchy Ramesh J , Lau Susanne , Llop Sabrina , Løset Mari , Marenholtz Ingo , Mason Dan , McCartney Daniel L , Melbye Mads , Melén Erik , Minica Camelia , Murray Clare S , Nijsten Tamar , Pardo Luba M , Pasmans Suzanne , Pennell Craig E , Rinnov Maria R , Santorelli Gillian , Schikowski Tamara , Sheehan Darina , Simpson Angela , Söderhäll Cilla , Thomas Laurent F , Thyssen Jacob P , Torrent Maties , van Beijsterveldt Toos , Visconti Alessia , Vonk Judith M. , Wang Carol A , Xu Cheng-Jian , Ziyab Ali H ,   UK-Translational Research Network in Dermatology,   BIOMAP consortium, Custovic Adnan , Meglio Paola Di , Duijts Liesbeth , Flohr Carsten , Irvine Alan D , Koppelman Gerard H , Lee Young-Ae , Reynolds Nick J , Smith Catherine , Langan Sinéad M , Paternoster Lavinia , Brown Sara J 
Published: January 2025

Background

Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. 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 andin vitromodelling to independently assess findings.

Results

The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 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 (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 nearIL7R) 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 modelledin vitroshowed a differential response according to rs10214237 genotype.

Conclusions

Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE viaIL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.