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[Preprint]. 2025 Sep 4:2025.01.24.25321071.
doi: 10.1101/2025.01.24.25321071.

Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modelling in vitro

Marie Standl  1   2 , Ashley Budu-Aggrey  3 , Luke J Johnston  4 , Martina S Elias  4 , S Hasan Arshad  5   6   7 , Peter Bager  8 , Veronique Bataille  9 , Helena Blakeway  3 , Klaus Bonnelykke  10 , Dorret Boomsma  11 , Ben M Brumpton  12 , Mariona Bustamante Pineda  13   14   15 , Archie Campbell  4 , John A Curtin  16 , Anders Eliasen  10 , João Ps Fadista  8 , Bjarke Feenstra  8 , Trine Gerner  17 , Carolina Medina Gomez  18 , Sarah Grosche  19 , Kristine B Gutzkow  20 , Anne-Sofie Halling  21 , Caroline Hayward  4 , John Henderson  3 , Esther Herrera-Luis  22 , John W Holloway  6   23 , Joukejan Hottenga  11 , Jonathan O'B Hourihane  24   25   26 , Chen Hu  27   28 , Kristian Hveem  12   29 , Amaia Irizar  15   30   31 , Benedicte Jacquemin  32 , Leon Jessen  10 , Sara Kress  33 , Ramesh J Kurukulaaratchy  5   6   7 , Susanne Lau  34 , Sabrina Llop  15   35 , Mari Løset  12   36 , Ingo Marenholtz  19   37 , Dan Mason  38 , Daniel L McCartney  4 , Mads Melbye  39   40   41 , Erik Melén  42 , Camelia Minica  11 , Clare S Murray  16 , Tamar Nijsten  28 , Luba M Pardo  28 , Suzanne Pasmans  28 , Craig E Pennell  43   44 , Maria R Rinnov  17   45 , Gillian Santorelli  38 , Tamara Schikowski  33 , Darina Sheehan  26   46   47 , Angela Simpson  16 , Cilla Söderhäll  48 , Laurent F Thomas  12   49   50 , Jacob P Thyssen  21 , Maties Torrent  51 , Toos van Beijsterveldt  11 , Alessia Visconti  9   52 , Judith M Vonk  53   54 , Carol A Wang  43   44 , Cheng-Jian Xu  55   56 , Ali H Ziyab  57 ; UK Translational Research Network in Dermatology; BIOMAP consortium; Adnan Custovic  58 , Paola Di Meglio  59   60 , Liesbeth Duijts  61   62 , Carsten Flohr  63 , Alan D Irvine  64 , Gerard H Koppelman  54   65 , Young-Ae Lee  19   34   37 , Nick J Reynolds  66   67 , Catherine Smith  60 , Sinéad M Langan  68   69 , Lavinia Paternoster  3   70 , Sara J Brown  4   71
Affiliations

Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modelling in vitro

Marie Standl et al. medRxiv. .

Update in

  • Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies.
    Standl M, Budu-Aggrey A, Johnston LJ, Elias MS, Arshad SH, Bager P, Bataille V, Blakeway H, Bønnelykke 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 AS, Hayward C, Henderson J, Herrera-Luis E, Holloway JW, Hottenga J, O'B Hourihane J, Hu C, Hveem K, Irizar A, Jacquemin B, Jessen L, Kress S, Kurukulaaratchy RJ, Lau S, Llop S, Løset M, Marenholz I, Mason D, McCartney DL, Melbye M, Melén E, Minica C, Murray CS, Nijsten T, Pardo LM, Pasmans S, Pennell CE, Rinnov MR, Santorelli G, Schikowski T, Sheehan D, Simpson A, Söderhäll C, Thomas LF, Thyssen JP, Torrent M, van Beijsterveldt T, Visconti A, Vonk JM, Wang CA, Xu CJ, Ziyab AH; UK Translational Research Network in Dermatology; BIOMAP Consortium; Custovic A, Di Meglio P, Duijts L, Flohr C, Irvine AD, Koppelman GH, Lee YA, Reynolds NJ, Smith C, Langan SM, Paternoster L, Brown SJ. Standl M, et al. Allergy. 2025 Aug;80(8):2201-2212. doi: 10.1111/all.16605. Epub 2025 Jun 4. Allergy. 2025. PMID: 40462597 Free PMC article.

Abstract

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 and in vitro modelling 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 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.

Conclusions: Interaction analysis and functional assessment provide 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 that only weak effects are likely to occur.

Keywords: Atopic eczema; atopic dermatitis; dog; environment; epidemiology; genetic; interaction; sibling.

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Conflict of interest statement

SJB has received research funding (but no personal financial benefits) from the Wellcome Trust (220875/Z/20/Z), UKRI, Medical Research Council, Rosetrees Trust, Stoneygates Trust, British Skin Foundation, Charles Wolfson Charitable Trust, anonymous donations from people with eczema, Unilever, Pfizer, Abbvie, Sosei-Heptares, Janssen, European Lead Factory (which includes multiple industry partners). SJB, AB-A, KB, ADI, GHK, CS, SML and LP have received funding from the BIOMAP-IMI consortium (EU H2020 project ref No 821511) which receives support from several pharmaceutical industry partners. LP has received honorarium payment for a scientific talk on eczema genetics from LEO Pharma. GHK reports grants from the Netherlands Lung Foundation, ZON-MW, Ubbo Emmius Foundation, TEVA the Netherlands, GSK, Vertex, outside the submitted work (money to institution). His institution received compensation for consultancy or lectures from Astra Zeneca, Boehringer Ingelheim and Sanofi.

Figures

Figure 1.
Figure 1.. Heatmap to summarise results of interaction analyses
Strength of colour indicates beta in which blue is positive and red is a negative direction of effect; diameter of circle indicates sample size; 14 nominally significant interactions (pint<0.05) are highlighted with black outline; one association was reported in only one cohort, so was not pursued further.
Figure 2.
Figure 2.. Forest plot showing interaction of dog exposure with rs10214237 in exposed and unexposed strata
Interaction analysis for discovery (N=18,045), replication (N=47,185) and combined meta-analysis (total N= 65,230) show the T allele of rs10214237 increases risk of atopic eczema only amongst those who are not exposed to a dog in the family home. Full names and study cohort descriptions are given in Additional file 6.
Figure 3.
Figure 3.. In vitro testing of the effects of dog allergen on primary human keratinocytes.
(3A) Dog allergen exposure stimulated a reduction in IL33 and TSLP mRNA but upregulation of CXCL8 (IL-8), CSF2, CCL2 and TNF; negative indicates keratinocyte media with dog allergen carrier solution; 5–12 donor isolates shown, bars represent SEM one-way ANOVA, Dunnet post hoc test compared to negative control, **p<0.01, ***p<0.001 ****p<0.0001. (3B) IL-10 signalling was the most significantly enriched Reactome pathway (4 out of 45 genes/proteins, FDR 7.71e-08). (3C-3E) Effects of IL-7 and dog allergen stimulation on primary human keratinocytes with different rs10214237 genotypes in which T is eczema risk allele; graphs represent the mean fold change in cytokine mRNA expression relative to the housekeeping gene EF1A, from 4 keratinocyte isolates with T:T genotype and 2 keratinocyte isolates from donors of C:C genotype; untreated indicates keratinocyte media only and negative is keratinocyte media with dog allergen carrier solution; BSA as 0.0002% included for as carrier protein for recombinant Il-7; two-way ANOVA with Dunnett’s post-hoc test, compared to the negative control, bars represent SEM, *p<0.05, **p<0.01.
See this image and copyright information in PMC

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