Gene–Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies
Marie Standl, Ashley Budu‐Aggrey, Luke Johnston, Martina S. Elias, Syed Hasan Arshad, Peter Bager, Véronique Bataille, Helena Blakeway, Klaus Bønnelykke, Dorret I. Boomsma, Ben Brumpton, Mariona Bustamante, Archie Campbell, John A. Curtin, Anders Eliasen, João Fadista, Bjarke Feenstra, Trine Gerner, Carolina Medina‐Gómez, Sarah Grosche, Kristine B. Gützkow, Anne‐Sofie Halling, Caroline Hayward, John Henderson, Esther Herrera‐Luis, John W. Holloway, Jouke‐Jan Hottenga, Jonathan O’B Hourihane, Chen Hu, Kristian Hveem, Amaia Irizar, Bénédicte Jacquemin, Leon Eyrich Jessen, Sara Kress, Ramesh Kurukulaaratchy, Susanne Lau, Sabrina Llop, Mari Løset, Ingo Marenholz, Dan Mason, Daniel L. McCartney, Mads Melbye, Erik Melén, Camelia C. Minică, Clare Murray, Tamar Nijsten, Luba M. Pardo, Suzanne G.M.A. Pasmans, Craig E. Pennell, Maria Rasmussen Rinnov, Gillian Santorelli, Tamara Schikowski, Darina Sheehan, Angela Simpson, Cilla Söderhäll, Laurent F. Thomas, Jacob P. Thyssen, Maties Torrent, Toos van Beijsterveldt, Alessia Visconti, Judith M. Vonk, Carol A. Wang, Cheng‐Jian Xu, Ali H. Ziyab, Adnan Čustović, Paola Di Meglio, Liesbeth Duijts, Carsten Flohr, Alan D. Irvine, Gerard H. Koppelman, Young‐Ae Lee, Nick J. Reynolds, Catherine Smith, Sinéad Langan, Lavinia Paternoster, Sara Brown
Abstract
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 (OR interaction = 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 (OR interaction = 0.84 [0.75–0.94] p = 0.003), but replication analysis was under‐powered (OR interaction = 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.