{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:28:54Z","timestamp":1790180934610,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["754425"],"award-info":[{"award-number":["754425"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational All"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Asthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome\u2010wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma\u2010associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs and asthma\u2010associated traits and assess expression quantitative trait locus (e\u2010QTLs) to reveal their downstream functional effects and find drug targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Association analyses between 128 asthma SNPs and associated traits (blood eosinophil numbers, atopy, airway obstruction, airway hyperresponsiveness) were conducted using regression modelling in population\u2010based studies (Lifelines <jats:italic>N<\/jats:italic>\u00a0=\u00a032,817\/Vlagtwedde\u2010Vlaardingen <jats:italic>N<\/jats:italic>\u00a0=\u00a01554) and an asthma cohort (Dutch Asthma genome\u2010wide association study <jats:italic>N<\/jats:italic>\u00a0=\u00a0917). Functional enrichment and pathway analysis were performed with genes linked to the significant SNPs by e\u2010QTL analysis. Genes were investigated to generate novel drug targets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 69 asthma SNPs that were associated with at least one trait, with 20 SNPs being associated with multiple traits. The SNP annotated to SMAD3 was the most pleiotropic. In total, 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy. We identified genetically driven pathways regulating eosinophilia. The largest network of eosinophilia contained two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma. Several novel targets were identified such as IL\u201018, CCR4, and calcineurin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Many asthma SNPs are associated with blood eosinophil counts and genetically driven molecular pathways of asthma\u2010associated traits were identified.<\/jats:p><\/jats:sec>","DOI":"10.1002\/clt2.12239","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T03:06:00Z","timestamp":1682046360000},"source":"Crossref","is-referenced-by-count":19,"title":["Association of asthma genetic variants with asthma\u2010associated traits reveals molecular pathways of\u00a0eosinophilic asthma"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1109-1756","authenticated-orcid":false,"given":"Zaid W.","family":"El\u2010Husseini","sequence":"first","affiliation":[{"name":"Department of Pediatric Pulmonology and Pediatric Allergology Beatrix Children's Hospital University of Groningen University Medical Center Groningen  Groningen The Netherlands"},{"name":"Groningen Research Institute for Asthma and COPD (GRIAC) University of Groningen University Medical Center Groningen  Groningen The Netherlands"},{"name":"Molecular Pharmacology Groningen Research Institute of Pharmacy  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith M.","family":"Vonk","sequence":"additional","affiliation":[{"name":"Groningen Research Institute for Asthma and COPD (GRIAC) University of Groningen University Medical Center Groningen  Groningen The Netherlands"},{"name":"Department of Epidemiology University of Groningen University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"van den Berge","sequence":"additional","affiliation":[{"name":"Groningen Research Institute for Asthma and COPD (GRIAC) University of Groningen University Medical Center Groningen  Groningen The Netherlands"},{"name":"Department of Pulmonary Diseases University of Groningen University Medical Center Groningen  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinoud","family":"Gosens","sequence":"additional","affiliation":[{"name":"Groningen Research Institute for Asthma and COPD (GRIAC) University of Groningen University Medical Center Groningen  Groningen The Netherlands"},{"name":"Molecular Pharmacology Groningen Research Institute of Pharmacy  Groningen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard H.","family":"Koppelman","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology and Pediatric Allergology Beatrix Children's Hospital University of Groningen University Medical Center Groningen  Groningen The Netherlands"},{"name":"Groningen Research Institute for Asthma and COPD (GRIAC) University of Groningen University Medical Center Groningen  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