{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:20:20Z","timestamp":1777414820415,"version":"3.51.4"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,10,9]],"date-time":"2019-10-09T00:00:00Z","timestamp":1570579200000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT084703MA"],"award-info":[{"award-number":["WT084703MA"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Experimental Allergy"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early\u2010life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>Our aim was to identify new loci interacting with ELTS exposure on time\u2010to\u2010asthma onset (TAO) in childhood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted genome\u2010wide interaction analyses of ELTS exposure on time\u2010to\u2010asthma onset in childhood in five European\u2010ancestry studies (totalling 8273 subjects) using Cox proportional\u2010hazard model. The results of all five genome\u2010wide analyses were meta\u2010analysed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The 13q21 locus showed genome\u2010wide significant interaction with ELTS exposure (<jats:italic>P<\/jats:italic>\u00a0=\u00a04.3\u00a0\u00d7\u00a010<jats:sup>\u22128<\/jats:sup> for rs7334050 within <jats:italic>KLHL1<\/jats:italic> with consistent results across the five studies). Suggestive interactions (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a05\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>) were found at three other loci: 20p12 (rs13037508 within <jats:italic>MACROD2<\/jats:italic>; <jats:italic>P<\/jats:italic>\u00a0=\u00a04.9\u00a0\u00d7\u00a010<jats:sup>\u22127<\/jats:sup>), 14q22 (rs7493885 near <jats:italic>NIN<\/jats:italic>; <jats:italic>P<\/jats:italic>\u00a0=\u00a02.9\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>) and 2p22 (rs232542 near <jats:italic>CYP1B1<\/jats:italic>; <jats:italic>P<\/jats:italic>\u00a0=\u00a04.1\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup>). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Clinical Relevance<\/jats:title><jats:p>We identified novel candidate genes interacting with ELTS exposure on time\u2010to\u2010asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.13476","type":"journal-article","created":{"date-parts":[[2019,8,5]],"date-time":"2019-08-05T06:29:24Z","timestamp":1564986564000},"page":"1342-1351","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Genome\u2010wide interaction study of early\u2010life smoking exposure on time\u2010to\u2010asthma onset in childhood"],"prefix":"10.1111","volume":"49","author":[{"given":"Pierre\u2010Emmanuel","family":"Sugier","sequence":"first","affiliation":[{"name":"Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Inserm, UMRS\u20101124 Universit\u00e9 Paris Descartes Paris France"},{"name":"Universit\u00e9 Pierre et Marie Curie Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chlo\u00e9","family":"Sarnowski","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Inserm, UMRS\u20101124 Universit\u00e9 Paris Descartes Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4890-4012","authenticated-orcid":false,"given":"Raquel","family":"Granell","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School University of Bristol Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Laprise","sequence":"additional","affiliation":[{"name":"D\u00e9partement des Sciences Fondamentales Universit\u00e9 du Qu\u00e9bec \u00e0 Chicoutimi Saguenay QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus J.","family":"Ege","sequence":"additional","affiliation":[{"name":"Dr von Hauner Children's Hospital Ludwig Maximilian University Munich Germany"},{"name":"Comprehensive Pneumology Center Munich (CPC\u2010M) German Center for Lung Research Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Margaritte\u2010Jeannin","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Inserm, UMRS\u20101124 Universit\u00e9 Paris Descartes Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8460-7667","authenticated-orcid":false,"given":"Marie\u2010H\u00e9l\u00e8ne","family":"Dizier","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology and Functional Genomics of Multifactorial Diseases Team, Inserm, UMRS\u20101124 Universit\u00e9 Paris Descartes Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cosetta","family":"Minelli","sequence":"additional","affiliation":[{"name":"Population Health &amp; Occupational Disease, National Heart and Lung Institute Imperial College London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam F.","family":"Moffatt","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, National Heart Lung Institute Imperial College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Lathrop","sequence":"additional","affiliation":[{"name":"McGill University and G\u00e9nome Qu\u00e9bec Innovation Centre Montr\u00e9al QC Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William O. C. M.","family":"Cookson","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, National Heart Lung Institute Imperial College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. John","family":"Henderson","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School University of Bristol Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"von Mutius","sequence":"additional","affiliation":[{"name":"Dr von Hauner Children's Hospital Ludwig Maximilian University Munich Germany"},{"name":"Comprehensive Pneumology Center Munich (CPC\u2010M) German Center for Lung Research Munich Germany"},{"name":"Institute for Asthma and Allergy Prevention Helmholtz Zentrum M\u00fcnchen \u2010 German Research Center for Environmental Health Neuherberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manolis","family":"Kogevinas","sequence":"additional","affiliation":[{"name":"ISGlobal Barcelona Spain"},{"name":"Universitat Pompeu Fabra (UPF) Barcelona Spain"},{"name":"CIBER Epidemiolog\u00eda y Salud P\u00fablica (CIBERESP) Madrid 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