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, Jacquemin 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, Custovic Adnan, Di Meglio Paola, 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
Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
German Center for Child and Adolescent Health (DZKJ), partner site Munich, Munich, Germany.
medRxiv. 2025 Sep 4:2025.01.24.25321071. doi: 10.1101/2025.01.24.25321071.
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 modelling to independently assess findings.
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 (OR=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=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered OR=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled showed a differential response according to rs10214237 genotype.
Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via , 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.
环境因素在包括特应性皮炎（AE）在内的复杂性状发病机制中起作用，需要更深入了解基因-环境相互作用（G*E）以明确疾病预防的病理机制。我们分析了来自16项欧洲研究的数据，以测试从全基因组关联研究中确定的24个最显著的AE相关基因座与18种早期生活环境因素之间的相互作用。我们使用另外10项研究进行复制测试，并进行建模以独立评估研究结果。
发现分析显示7种环境因素（抗生素使用、养猫、养狗、母乳喂养、年长兄弟姐妹、吸烟和洗涤习惯）与至少一种已确定的AE变异之间存在相互作用的提示性证据（p<0.05），总共14种相互作用（最大样本量=25,339）。在复制分析中（最大样本量=252,040），狗暴露*rs10214237（位于5号染色体p13.2上靠近IL7R）名义上具有显著性（OR=0.91[0.83-0.99]，P=0.025），仅在未接触狗的个体中观察到T等位基因的风险效应。在发现分析中，对于兄弟姐妹，观察到与rs10214237有类似的相互作用（OR=0.84[0.75-0.94]，P=0.003），但复制分析的效能不足（OR=1.09[0.82-1.46]）。Rs10214237纯合风险基因型与人类角质形成细胞中较低的IL-7R表达相关，并且根据rs10214237基因型，模拟的狗暴露显示出不同的反应。
相互作用分析和功能评估提供了证据，表明早期生活中接触狗可能通过改变rs10214237对AE的遗传效应，支持观察性流行病学显示养狗具有保护作用。此处研究的其他G*E缺乏证据意味着可能仅发生微弱效应。
