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Multi-ancestry genome-wide association study of asthma exacerbations

dc.contributor.authorHerrera Luis, Esther
dc.contributor.authorOrtega, Victor E.
dc.contributor.authorAmpleford, Elizabeth J.
dc.contributor.authorSio, Yang Yie
dc.contributor.authorGranell, Raquel
dc.contributor.authorde Roos, Emmely
dc.contributor.authorTerzikhan, Natalie
dc.contributor.authorElorduy Vergara, Ernesto
dc.contributor.authorHernández Pacheco, Natalia
dc.contributor.authorPérez García, Javier
dc.contributor.authorMartín González, Elena
dc.contributor.authorLorenzo Díaz, Fabián
dc.contributor.authorHashimoto, Simone
dc.contributor.authorBrinkman, Paul
dc.contributor.authorU-BIOPRED Study Group
dc.contributor.authorJorgensen, Andrea L.
dc.contributor.authorYan, Qi
dc.contributor.authorForno, Erick
dc.contributor.authorVijverberg, Susanne J.
dc.contributor.authorLethem, Ryan
dc.contributor.authorEspuela Ortiz, Antonio
dc.contributor.authorGorenjak, Mario
dc.contributor.authorEng, Celeste
dc.contributor.authorGonzález Pérez, Ruperto
dc.contributor.authorHernández Pérez, José M.
dc.contributor.authorPoza Guedes, Paloma
dc.contributor.authorSardón Prado, Olaia
dc.contributor.authorCorcuera Elosegui, Paula
dc.contributor.authorHawkins, Greg A.
dc.contributor.authorMarsico, Annalisa
dc.contributor.authorBahmer, Thomas
dc.contributor.authorRabe, Klaus F.
dc.contributor.authorHansen, Gesine
dc.contributor.authorKopp, Matthias Volkmar
dc.contributor.authorRios, Raimon
dc.contributor.authorCruz Carmona, María Jesús
dc.contributor.authorGonzález Barcala, Francisco Javier
dc.contributor.authorOlaguibel, José María
dc.contributor.authorPlaza, Vicente
dc.contributor.authorQuirce, Santiago
dc.contributor.authorCanino, Glorisa
dc.contributor.authorCloutier, Michelle
dc.contributor.authorDel Pozo, Victoria
dc.contributor.authorRodríguez Santana, José R.
dc.contributor.authorKorta Murua, José Javier
dc.contributor.authorVillar, Jesús
dc.contributor.authorPotočnik, Uroš
dc.contributor.authorFigueiredo, Camila
dc.contributor.authorKabesch, Michael
dc.contributor.authorMukhopadhyay, Somnath
dc.contributor.authorPirmohamed, Munir
dc.contributor.authorHawcutt, Daniel B.
dc.contributor.authorMelén, Erik
dc.contributor.authorPalmer, Colin N.
dc.contributor.authorTurner, Steven
dc.contributor.authorMaitland-van der Zee, Anke H.
dc.contributor.authorvon Mutius, Erika
dc.contributor.authorCeledón, Juan C.
dc.contributor.authorBrusselle, Guy
dc.contributor.authorChew, Fook Tim
dc.contributor.authorBleecker, Eugene
dc.contributor.authorMeyers, Deborah
dc.contributor.authorBurchard, Esteban G.
dc.contributor.authorPino Yanes, María
dc.date.accessioned2022-10-25T13:39:46Z
dc.date.available2022-10-25T13:39:46Z
dc.date.issued2022-06
dc.identifier.citationPediatric Allergy and Immunology 33(6) : (2022) // Article ID e13802es_ES
dc.identifier.issn0905-6157
dc.identifier.issn1399-3038
dc.identifier.urihttp://hdl.handle.net/10810/58186
dc.description.abstractBackground: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) 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. Methods: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p <= 5 x 10(-5)) were assessed for replication in 36,477 European and 1078 non-European 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. Results: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 x 10(-6) and replication: ORT allele = 0.89, p = 5.35 x 10(-3)) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 x 10(-5) and replication: ORC allele = 0.89, p = 1.30 x 10(-2)). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.es_ES
dc.description.sponsorshipThis work was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033, and the European Regional Development Fund “ERDF A way of making Europe” by the European Union (SAF2017-83417R), by MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00) and by the Allergopharma-EAACI award 2021. This study was also supported by the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020. GALA II and SAGE studies were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL141992, and R01HL141845), National Institute of Health and Environmental Health Sciences (R01ES015794 and R21ES24844); the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443, and R56MD013312); the National Institute of General Medical Sciences (NIGMS) (RL5GM118984); the Tobacco-Related Disease Research Program (24RT-0025 and 27IR-0030); and the National Human Genome Research Institute (NHGRI) (U01HG009080) to EGB. The PACMAN study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The Slovenia study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) and from SysPharmPediA grant, co-financed by the Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and were established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. Genotyping of samples from BREATHE, PAGES, and GoSHARE was funded by AC15/00015 and conducted at the Genotyping National Centre (CeGEN) CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019). ALSPAC was supported by the UK Medical Research Council and Wellcome (102215/2/13/2) and the University of Bristol. The Swedish Heart-Lung Foundation, the Swedish Research Council, and Region Stockholm (ALF project and database maintenance) funded the BAMSE study. The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. U-BIOPRED was funded by the Innovative Medicines Initiative (IMI) Joint Undertaking, under grant agreement no. 115010, resources for which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and kind contributions from companies in the European Federation of Pharmaceutical Industries and Associations (EFPIA). Genotyping of samples from GEMAS and MEGA studies was funded by the Spanish Ministry of Science and Innovation (SAF2017-87417R) at the Spanish National Cancer Research Centre, in the Human Genotyping lab, a member of CeGen, PRB3, and was supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The genotyping of GEMAS was also partially funded by Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC19/17). The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. ALLIANCE Cohort was funded by grants from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) as part of the German Centre for Lung Research (DZL) funding. The Hartford-Puerto Rico study was funded by the U.S. National Institutes of Health (grant HL07966 to JCC). MP-Y was funded by the Ramón y Cajal Program (RYC-2015-17205) by MCIN/AEI/10.13039/501100011033 and by the European Social Fund “ESF Investing in your future”. MP-Y and JV were supported by CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain (CB/06/06/1088). EH-L was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” (PRE2018-083837). JP-G was supported by a fellowship awarded by Spanish Ministry of Universities (FPU19/02175). AE-O reports funding from the Spanish Ministry of Science, Innovation, and Universities (MICIU) and Universidad de La Laguna (ULL). NH-P was supported by a Medium-Term Research Fellowship by the European Academy of Allergy and Clinical Immunology (EAACI) and a Long-Term Research Fellowship by the European Respiratory Society (ERS) (LTRF202101-00861). UP and MG were supported by the Ministry of Education, Science and Sport of the Republic of Slovenia, grant PERMEABLE (contract number C3330-19-252012). SCSGES results were contributed by authors FTC and YYS. FTC has received research support from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network (SIgN), National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore); Grant Numbers: N-154-000-038-001, R-154-000-191-112, R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112, R-154-000-A08-592, R-154-000-A27-597, R-154-000-A91-592, R-154-000-A95-592, R-154-000-B99-114, BMRC/01/1/21/18/077, BMRC/04/1/21/19/315, SIgN-06-006, SIgN-08-020, NMRC/1150/2008, and H17/01/a0/008. F.T.C. has received consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. YYS has received research support from the NUS Resilience & Growth Postdoctoral Fellowships with grant number: R-141-000-036-281. QY conducted the analysis from Hartford-Puerto Rico and United Kingdom Biobank studies. QY was funded by the U.S. National Institutes of Health (HL138098). All funding agencies had no role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The views expressed are those of the authors and not necessarily those of the any funder, National Health Service (NHS), the National Institute for Health Research (NIHR) or the United Kingdom Department of Health.es_ES
dc.language.isoenges_ES
dc.publisherWileyes_ES
dc.relationinfo:eu-repo/grantAgreement/EC/FP7/115010es_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/SAF2017-83417Res_ES
dc.relationinfo:eu-repo/grantAgreement/MICINN/PID2020-116274RB-I00es_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/SAF2017-87417Res_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/RYC-2015-17205es_ES
dc.relationinfo:eu-repo/grantAgreement/MINECO/PRE2018-083837es_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.subjectasthma exacerbationses_ES
dc.subjectEXTL2es_ES
dc.subjectGWASes_ES
dc.subjectPANK1es_ES
dc.subjectsingle-nucleotide polymorphismes_ES
dc.titleMulti-ancestry genome-wide association study of asthma exacerbationses_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.es_ES
dc.rights.holderAtribución 3.0 España*
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/10.1111/pai.13802es_ES
dc.identifier.doi10.1111/pai.13802
dc.contributor.funderEuropean Commission
dc.departamentoesPediatríaes_ES
dc.departamentoeuPediatriaes_ES


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© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as © 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.