{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T09:35:10Z","timestamp":1793093710678,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["QLK4-CT-2001-00250"],"award-info":[{"award-number":["QLK4-CT-2001-00250"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["FOOD-CT-2006-31708"],"award-info":[{"award-number":["FOOD-CT-2006-31708"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["KBBE-2007-2-2-06"],"award-info":[{"award-number":["KBBE-2007-2-2-06"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["250268"],"award-info":[{"award-number":["250268"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor\u2019s diagnosis. Single-nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.16\u20132.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33\u20130.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 [95% CI, 1.09\u20132.67]; and aOR, 0.48 [95% CI, 0.30\u20130.76], respectively).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene\u2013environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201507-1493oc","type":"journal-article","created":{"date-parts":[[2015,11,17]],"date-time":"2015-11-17T16:24:21Z","timestamp":1447777461000},"page":"889-897","source":"Crossref","is-referenced-by-count":147,"title":["The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21"],"prefix":"10.1093","volume":"193","author":[{"given":"Georg J.","family":"Loss","sequence":"first","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Ludwig Maximilians University Munich, Munich, Germany"},{"name":"Department of Pediatrics, University of California, San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Depner","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Ludwig Maximilians University Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Hose","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Ludwig Maximilians University Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5764-1528","authenticated-orcid":false,"given":"Jon","family":"Genuneit","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Karvonen","sequence":"additional","affiliation":[{"name":"Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Hyv\u00e4rinen","sequence":"additional","affiliation":[{"name":"Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Roduit","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital, University of Z\u00fcrich, Z\u00fcrich, Switzerland"},{"name":"Christine K\u00fchne\u2013Center for Allergy Research and Education, Davos, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kabesch","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pneumology and Allergy, KUNO Children\u2019s University Hospital Regensburg, Regensburg, Germany"},{"name":"Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Lauener","sequence":"additional","affiliation":[{"name":"Christine K\u00fchne\u2013Center for Allergy Research and Education, Davos, Switzerland"},{"name":"Children\u2019s Hospital of Eastern Switzerland, St. Gallen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra Ina","family":"Pfefferle","sequence":"additional","affiliation":[{"name":"Comprehensive Biomaterial Bank Marburg CBBM, Center for Tumor Biology and Immunology, Faculty of Medicine, Philipp University of Marburg, Marburg, Germany"},{"name":"German Center for Lung Research, Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha","family":"Pekkanen","sequence":"additional","affiliation":[{"name":"Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland"},{"name":"Department of Public Health, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Charles","family":"Dalphin","sequence":"additional","affiliation":[{"name":"Department of Respiratory Disease, University of Besan\u00e7on, University Hospital, Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef","family":"Riedler","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital Schwarzach, Schwarzach, Austria"},{"name":"Teaching Hospital of Paracelsus Private Medical University of Salzburg, Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Braun-Fahrl\u00e4nder","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute, Basel, Switzerland"},{"name":"University of Basel, Basel, Switzerland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"von Mutius","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Ludwig Maximilians University Munich, Munich, Germany"},{"name":"German Center for Lung Research, Comprehensive Pneumology Center Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6643-3923","authenticated-orcid":false,"given":"Markus J.","family":"Ege","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Ludwig Maximilians University Munich, Munich, Germany"},{"name":"German Center for Lung Research, Comprehensive Pneumology Center Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,4,15]]},"reference":[{"key":"2026032100033925100_bib1","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/nri2871","article-title":"Farm living: effects on childhood asthma and allergy","volume":"10","author":"von Mutius","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"2026032100033925100_bib2","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1398-9995.2006.01009.x","article-title":"The PASTURE project: EU support for the improvement of knowledge about risk factors and preventive factors for atopy in Europe","volume":"61","author":"von Mutius","year":"2006","journal-title":"Allergy"},{"key":"2026032100033925100_bib3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jaci.2014.08.044","article-title":"Consumption of unprocessed cow\u2019s milk protects infants from common respiratory infections","volume":"135","author":"Loss","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib4","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1016\/j.jaci.2012.03.013","article-title":"Protection from childhood asthma and allergy in Alpine farm environments\u2014the GABRIEL Advanced Studies","volume":"129","author":"Illi","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib5","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.jaci.2012.04.049","article-title":"Farming environments and childhood atopy, wheeze, lung function, and exhaled nitric oxide","volume":"130","author":"Fuchs","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1164\/rccm.201307-1198OC","article-title":"Clinical and epidemiologic phenotypes of childhood asthma","volume":"189","author":"Depner","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100033925100_bib7","doi-asserted-by":"crossref","first-page":"278","DOI":"10.3389\/fmicb.2013.00278","article-title":"Molecular epidemiology of respiratory viruses in virus-induced asthma","volume":"4","author":"Tsukagoshi","year":"2013","journal-title":"Front Microbiol"},{"key":"2026032100033925100_bib8","doi-asserted-by":"crossref","first-page":"7418","DOI":"10.1128\/JVI.02290-09","article-title":"The ABCs of rhinoviruses, wheezing, and asthma","volume":"84","author":"Gern","year":"2010","journal-title":"J Virol"},{"key":"2026032100033925100_bib9","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nm.2768","article-title":"Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment","volume":"18","author":"Holt","year":"2012","journal-title":"Nat Med"},{"key":"2026032100033925100_bib10","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1056\/NEJMoa1211592","article-title":"Rhinovirus wheezing illness and genetic risk of childhood-onset asthma","volume":"368","author":"Cal\u0131\u015fkan","year":"2013","journal-title":"N Engl J Med"},{"key":"2026032100033925100_bib11","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-065X.2011.01029.x","article-title":"The genetics of asthma and allergic disease: a 21st century perspective","volume":"242","author":"Ober","year":"2011","journal-title":"Immunol Rev"},{"key":"2026032100033925100_bib12","article-title":"Chr17q21 modifies environmental effects on respiratory infections in infancy and effects on asthma [abstract]","volume":"46","author":"Loss","year":"2015","journal-title":"Eur Respir J"},{"key":"2026032100033925100_bib13","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1016\/j.jaci.2013.12.1044","article-title":"Increased food diversity in the first year of life is inversely associated with allergic diseases","volume":"133","author":"Roduit","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib14","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jaci.2015.02.024","article-title":"Association between respiratory infections in early life and later asthma is independent of virus type","volume":"136","author":"B\u00f8nnelykke","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib15","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1136\/bmj.299.6710.1259","article-title":"Hay fever, hygiene, and household size","volume":"299","author":"Strachan","year":"1989","journal-title":"BMJ"},{"key":"2026032100033925100_bib16","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.jaci.2013.05.043","article-title":"Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood","volume":"132","author":"Penders","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib17","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1542\/peds.2011-2825","article-title":"Respiratory tract illnesses during the first year of life: effect of dog and cat contacts","volume":"130","author":"Bergroth","year":"2012","journal-title":"Pediatrics"},{"key":"2026032100033925100_bib18","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1056\/NEJMoa1007302","article-title":"Exposure to environmental microorganisms and childhood asthma","volume":"364","author":"Ege","year":"2011","journal-title":"N Engl J Med"},{"key":"2026032100033925100_bib19","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.jaci.2005.12.1307","article-title":"Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children","volume":"117","author":"Ege","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib20","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/S0140-6736(02)09641-1","article-title":"Expression of CD14 and Toll-like receptor 2 in farmers\u2019 and non-farmers\u2019 children","volume":"360","author":"Lauener","year":"2002","journal-title":"Lancet"},{"key":"2026032100033925100_bib21","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1136\/thx.2005.049403","article-title":"Inhalation of stable dust extract prevents allergen induced airway inflammation and hyperresponsiveness","volume":"61","author":"Peters","year":"2006","journal-title":"Thorax"},{"key":"2026032100033925100_bib22","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1016\/j.jaci.2007.03.023","article-title":"Acinetobacter lwoffii and Lactococcus lactis strains isolated from farm cowsheds possess strong allergy-protective properties","volume":"119","author":"Debarry","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib23","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1084\/jem.20090845","article-title":"Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78","volume":"206","author":"Conrad","year":"2009","journal-title":"J Exp Med"},{"key":"2026032100033925100_bib24","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.jaci.2008.05.016","article-title":"Animal shed Bacillus licheniformis spores possess allergy-protective as well as inflammatory properties","volume":"122","author":"Vogel","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib25","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.jaci.2010.05.011","article-title":"Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization","volume":"126","author":"Peters","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib26","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S2213-2600(13)70145-0","article-title":"Prenatal and childhood infections: implications for the development and treatment of childhood asthma","volume":"1","author":"Fuchs","year":"2013","journal-title":"Lancet Respir Med"},{"key":"2026032100033925100_bib27","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.jaci.2010.09.041","article-title":"Gene-environment interaction for childhood asthma and exposure to farming in Central Europe","volume":"127","author":"Ege","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100033925100_bib28","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1007\/s10654-013-9837-4","article-title":"Comparisons of power of statistical methods for gene-environment interaction analyses","volume":"28","author":"Ege","year":"2013","journal-title":"Eur J Epidemiol"},{"key":"2026032100033925100_bib29","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1056\/NEJMoa0806604","article-title":"Effect of 17q21 variants and smoking exposure in early-onset asthma","volume":"359","author":"Bouzigon","year":"2008","journal-title":"N Engl J Med"},{"key":"2026032100033925100_bib30","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1183\/09031936.00164109","article-title":"Changes in the FEV\u2081\/FVC ratio during childhood and adolescence: an intercontinental study","volume":"36","author":"Quanjer","year":"2010","journal-title":"Eur Respir J"},{"key":"2026032100033925100_bib31","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1183\/09031936.00154509","article-title":"17q21 variants modify the association between early respiratory infections and asthma","volume":"36","author":"Smit","year":"2010","journal-title":"Eur Respir J"},{"key":"2026032100033925100_bib32","doi-asserted-by":"crossref","first-page":"e13795","DOI":"10.1371\/journal.pone.0013795","article-title":"Evidence for significant overlap between common risk variants for Crohn\u2019s disease and ankylosing spondylitis","volume":"5","author":"Laukens","year":"2010","journal-title":"PLoS One"},{"key":"2026032100033925100_bib33","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.jaci.2010.05.026","article-title":"The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children","volume":"126","author":"Sim\u00f5es","year":"2010","journal-title":"J Allergy Clin Immunol"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/193\/8\/889\/67255331\/ajrccm_193_8_889.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/193\/8\/889\/67255331\/ajrccm_193_8_889.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:03:46Z","timestamp":1774065826000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/193\/8\/889\/8508861"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2016,4,15]]},"published-print":{"date-parts":[[2016,4,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201507-1493oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,4]]},"published":{"date-parts":[[2016,4]]}}}