Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies

Marie Standl; Ashley Budu-Aggrey; Luke J Johnston; Martina S Elias; S Hasan Arshad; Peter Bager; Veronique Bataille; Helena Blakeway; Klaus Bønnelykke; Dorret Boomsma; Ben M Brumpton; Mariona Bustamante Pineda; Archie Campbell; John A Curtin; Anders Eliasen; João P S Fadista; Bjarke Feenstra; Trine Gerner; Carolina Medina-Gomez; Sarah Grosche; Kristine B Gutzkow; Anne-Sofie Halling; Caroline Hayward; John Henderson; Esther Herrera-Luis; John W Holloway; Joukejan Hottenga; Jonathan O'B Hourihane; Chen Hu; Kristian Hveem; Amaia Irizar; Benedicte Jacquemi; Leon Jessen; Sara Kress; Ramesh J Kurukulaaratchy; Susanne Lau; Sabrina Llop; Mari Løset; Ingo Marenholz; Dan Mason; Daniel L McCartney; Mads Melbye; Erik Melén; Camelia Minica; Clare S Murray; Tamar Nijsten; Luba M Pardo; Suzanne Pasmans; Craig E Pennell; Maria  R. Rinnov; Jacob P Thyssen; UK Translational Research Network in Dermatology; BIOMAP consortium

doi:10.1111/all.16605

Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies

Marie Standl, Ashley Budu-Aggrey, Luke J Johnston, Martina S Elias, S Hasan Arshad, Peter Bager, Veronique Bataille, Helena Blakeway, Klaus Bønnelykke, Dorret Boomsma, Ben M Brumpton, Mariona Bustamante Pineda, Archie Campbell, John A Curtin, Anders Eliasen, João P S Fadista, Bjarke Feenstra, Trine Gerner, Carolina Medina-Gomez, Sarah GroscheKristine B Gutzkow, Anne-Sofie Halling, Caroline Hayward, John Henderson, Esther Herrera-Luis, John W Holloway, Joukejan Hottenga, Jonathan O'B Hourihane, Chen Hu, Kristian Hveem, Amaia Irizar, Benedicte Jacquemi, Leon Jessen, Sara Kress, Ramesh J Kurukulaaratchy, Susanne Lau, Sabrina Llop, Mari Løset, Ingo Marenholz, Dan Mason, Daniel L McCartney, Mads Melbye, Erik Melén, Camelia Minica, Clare S Murray, Tamar Nijsten, Luba M Pardo, Suzanne Pasmans, Craig E Pennell, Maria R. Rinnov, Jacob P Thyssen, UK Translational Research Network in Dermatology, BIOMAP consortium

3 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Allergy
Volume	80
Issue number	8
Pages (from-to)	2201-2212
Number of pages	12
ISSN	0105-4538
DOIs	https://doi.org/10.1111/all.16605
Publication status	Published - Aug 2025

Keywords

Animals
Dermatitis, Atopic/epidemiology
Dogs
Gene-Environment Interaction
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Polymorphism, Single Nucleotide
Risk Factors

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Standl, M., Budu-Aggrey, A., Johnston, L. J., Elias, M. S., Arshad, S. H., Bager, P., Bataille, V., Blakeway, H., Bønnelykke, K., Boomsma, D., Brumpton, B. M., Bustamante Pineda, M., Campbell, A., Curtin, J. A., Eliasen, A., Fadista, J. P. S., Feenstra, B., Gerner, T., Medina-Gomez, C., ... BIOMAP consortium (2025). Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies. Allergy, 80(8), 2201-2212. https://doi.org/10.1111/all.16605

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, 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, 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 , Thyssen, JP, UK Translational Research Network in Dermatology & BIOMAP consortium 2025, 'Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies', Allergy, vol. 80, no. 8, pp. 2201-2212. https://doi.org/10.1111/all.16605

@article{951f9827a90d424488066465728a0503,

title = "Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies",

abstract = "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.",

keywords = "Animals, Dermatitis, Atopic/epidemiology, Dogs, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Risk Factors",

author = "Marie Standl and Ashley Budu-Aggrey and Johnston, \{Luke J\} and Elias, \{Martina S\} and Arshad, \{S Hasan\} and Peter Bager and Veronique Bataille and Helena Blakeway and Klaus B{\o}nnelykke and Dorret Boomsma and Brumpton, \{Ben M\} and \{Bustamante Pineda\}, Mariona and Archie Campbell and Curtin, \{John A\} and Anders Eliasen and Fadista, \{Jo{\~a}o P S\} and Bjarke Feenstra and Trine Gerner and Carolina Medina-Gomez and Sarah Grosche and Gutzkow, \{Kristine B\} and Anne-Sofie Halling and Caroline Hayward and John Henderson and Esther Herrera-Luis and Holloway, \{John W\} and Joukejan Hottenga and \{O'B Hourihane\}, Jonathan and Chen Hu and Kristian Hveem and Amaia Irizar and Benedicte Jacquemi and Leon Jessen and Sara Kress and Kurukulaaratchy, \{Ramesh J\} and Susanne Lau and Sabrina Llop and Mari L{\o}set and Ingo Marenholz and Dan Mason and McCartney, \{Daniel L\} and Mads Melbye and Erik Mel{\'e}n and Camelia Minica and Murray, \{Clare S\} and Tamar Nijsten and Pardo, \{Luba M\} and Suzanne Pasmans and Pennell, \{Craig E\} and Rinnov, \{Maria R.\} and Thyssen, \{Jacob P\} and \{UK Translational Research Network in Dermatology\} and \{BIOMAP consortium\}",

note = "{\textcopyright} 2025 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley \& Sons Ltd.",

year = "2025",

month = aug,

doi = "10.1111/all.16605",

language = "English",

volume = "80",

pages = "2201--2212",

journal = "Allergy",

issn = "0105-4538",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "8",

}

TY - JOUR

T1 - Gene-Environment Interaction Affects Risk of Atopic Eczema

T2 - Population and In Vitro Studies

AU - Standl, Marie

AU - Budu-Aggrey, Ashley

AU - Johnston, Luke J

AU - Elias, Martina S

AU - Arshad, S Hasan

AU - Bager, Peter

AU - Bataille, Veronique

AU - Blakeway, Helena

AU - Bønnelykke, Klaus

AU - Boomsma, Dorret

AU - Brumpton, Ben M

AU - Bustamante Pineda, Mariona

AU - Campbell, Archie

AU - Curtin, John A

AU - Eliasen, Anders

AU - Fadista, João P S

AU - Feenstra, Bjarke

AU - Gerner, Trine

AU - Medina-Gomez, Carolina

AU - Grosche, Sarah

AU - Gutzkow, Kristine B

AU - Halling, Anne-Sofie

AU - Hayward, Caroline

AU - Henderson, John

AU - Herrera-Luis, Esther

AU - Holloway, John W

AU - Hottenga, Joukejan

AU - O'B Hourihane, Jonathan

AU - Hu, Chen

AU - Hveem, Kristian

AU - Irizar, Amaia

AU - Jacquemi, Benedicte

AU - Jessen, Leon

AU - Kress, Sara

AU - Kurukulaaratchy, Ramesh J

AU - Lau, Susanne

AU - Llop, Sabrina

AU - Løset, Mari

AU - Marenholz, Ingo

AU - Mason, Dan

AU - McCartney, Daniel L

AU - Melbye, Mads

AU - Melén, Erik

AU - Minica, Camelia

AU - Murray, Clare S

AU - Nijsten, Tamar

AU - Pardo, Luba M

AU - Pasmans, Suzanne

AU - Pennell, Craig E

AU - Rinnov, Maria R.

AU - Thyssen, Jacob P

AU - UK Translational Research Network in Dermatology

AU - BIOMAP consortium

PY - 2025/8

Y1 - 2025/8

N2 - 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.

AB - 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.

KW - Animals

KW - Dermatitis, Atopic/epidemiology

KW - Dogs

KW - Gene-Environment Interaction

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

UR - https://www.scopus.com/pages/publications/105007759291

U2 - 10.1111/all.16605

DO - 10.1111/all.16605

M3 - Journal article

C2 - 40462597

SN - 0105-4538

VL - 80

SP - 2201

EP - 2212

JO - Allergy

JF - Allergy

IS - 8

ER -

Gene-Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies

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