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The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi\u2010ancestry meta\u2010analysis of genome\u2010wide association studies (meta\u2010GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A meta\u2010GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics\/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6\u00a0million genetic variants. Suggestively associated variants (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0\u2264\u00a05\u00a0\u00d7\u00a010\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) were assessed for replication in 36,477 European and 1078 non\u2010European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic\/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      One hundred and twenty\u2010six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010\u00a0located at\u00a0vascular cell adhesion molecule\u20101\/exostosin like\u00a0glycosyltransferase\u20102 (\n                      <jats:italic>VCAM1<\/jats:italic>\n                      \/\n                      <jats:italic>EXTL2<\/jats:italic>\n                      )\u00a0(discovery: odds ratio (OR\n                      <jats:sub>T allele<\/jats:sub>\n                      )\u00a0=\u00a00.82,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a09.05\u00a0\u00d7\u00a010\n                      <jats:sup>\u22126<\/jats:sup>\n                      and replication: OR\n                      <jats:sub>T allele<\/jats:sub>\n                      \u00a0=\u00a00.89,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a05.35\u00a0\u00d7\u00a010\n                      <jats:sup>\u22123<\/jats:sup>\n                      ) and rs943126 from\u00a0pantothenate kinase\u00a01 (\n                      <jats:italic>PANK1<\/jats:italic>\n                      ) (discovery: OR\n                      <jats:sub>C allele<\/jats:sub>\n                      \u00a0=\u00a00.85,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a03.10\u00a0\u00d7\u00a010\n                      <jats:sup>\u22125<\/jats:sup>\n                      and replication: OR\n                      <jats:sub>C allele<\/jats:sub>\n                      \u00a0=\u00a00.89,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a01.30\u00a0\u00d7\u00a010\n                      <jats:sup>\u22122<\/jats:sup>\n                      ). Both variants regulate gene expression\u00a0of genes where they locate and DNA methylation levels of nearby genes in whole blood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This multi\u2010ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/pai.13802","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T08:11:11Z","timestamp":1654675871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Multi\u2010ancestry genome\u2010wide association study of asthma exacerbations"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-5454","authenticated-orcid":false,"given":"Esther","family":"Herrera\u2010Luis","sequence":"first","affiliation":[{"name":"Genomics and Health Group Department of Biochemistry, Microbiology, Cell Biology and Genetics Universidad de La Laguna (ULL)  San Crist\u00f3bal de La Laguna, Tenerife Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor E.","family":"Ortega","sequence":"additional","affiliation":[{"name":"Division of Respiratory Medicine Department of Internal Medicine Mayo Clinic  Scottsdale Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Ampleford","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Center for Precision Medicine Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang Yie","family":"Sio","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences National University of Singapore  Singapore City Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4890-4012","authenticated-orcid":false,"given":"Raquel","family":"Granell","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU) Population Health Sciences Bristol Medical School University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmely","family":"de Roos","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Erasmus University Medical Center  Rotterdam The Netherlands"},{"name":"Department of Respiratory Medicine Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Terzikhan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology Erasmus University Medical Center  Rotterdam The Netherlands"},{"name":"Department of Respiratory Medicine Ghent University Hospital  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto\u00a0Elorduy","family":"Vergara","sequence":"additional","affiliation":[{"name":"Institute of Computation Biology Helmholtz Zentrum M\u00fcnchen German Research Center for Environmental Health  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-1847","authenticated-orcid":false,"given":"Natalia","family":"Hernandez\u2010Pacheco","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Education S\u00f6dersjukhuset Karolinska Institutet  Stockholm Sweden"},{"name":"CIBER de Enfermedades Respiratorias (CIBERES)  Madrid 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of Biochemistry, Microbiology, Cell Biology and Genetics Universidad de La Laguna (ULL)  San Crist\u00f3bal de La Laguna, Tenerife Spain"},{"name":"Instituto Universitario de Enfermedades Tropicales y Salud P\u00fablica de Canarias (IUETSPC) Universidad de La Laguna (ULL)  San Crist\u00f3bal de La Laguna, Tenerife Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8995-3817","authenticated-orcid":false,"given":"Simone","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Amsterdam University Medical Center University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Brinkman","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Amsterdam University Medical Center University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"U\u2010BIOPRED Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"Department of Health Data Science Institute of Population Health University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5236-9673","authenticated-orcid":false,"given":"Qi","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Columbia University Irving Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6497-9885","authenticated-orcid":false,"given":"Erick","family":"Forno","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary Medicine UPMC Children's Hospital of Pittsburgh University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4579-4081","authenticated-orcid":false,"given":"Susanne J.","family":"Vijverberg","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"},{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Faculty of Science Utrecht University  Utrecht The Netherlands"},{"name":"Department of Paediatric Respiratory Medicine and Allergy Emma's Children Hospital Amsterdam UMC University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Lethem","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit (IEU) Population Health Sciences Bristol Medical School University of Bristol  Bristol 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Pneumology  Grosshansdorf Germany"},{"name":"Airway Research Center North (ARCN) Members of the Germany Center for Lung Research (DZL)  Grosshansdorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus F.","family":"Rabe","sequence":"additional","affiliation":[{"name":"LungenClinic Grosshansdorf, Pneumology  Grosshansdorf Germany"},{"name":"Airway Research Center North (ARCN) Members of the Germany Center for Lung Research (DZL)  Grosshansdorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gesine","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pneumology, Allergology and Neonatology Hannover Medical School  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias Volkmar","family":"Kopp","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pneumology &amp; Allergology University Medical Center Schleswig\u2010Holstein  L\u00fcbeck 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