Multi-ancestry genome-wide association study of asthma exacerbations
Herrera-Luis, Esther (Universidad de La Laguna. Departamento de Bioquímica, Microbiología, Biología Celular y Genética)
Ortega, Victor E. (División de Medicina Respiratoria. Departamento de Medicina Interna. Mayo Clinic)
Ampleford, Elizabeth J. (Department of Internal Medicine. Center for Precision Medicine. Wake Forest School of Medicine)
Sio, Yang Yie (Department of Biological Sciences. National University of Singapore)
Granell, Raquel (MRC Integrative Epidemiology Unit (IEU). Population Health Sciences. Bristol Medical School. University of Bristol)
de Roos, Emmely (Department of Respiratory Medicine. Ghent University Hospital)
Terzikhan, Natalie (Department of Respiratory Medicine. Ghent University Hospital)
Vergara, Ernesto Elorduy (Institute of Computation Biology. Helmholtz Zentrum München. German Research Center for Environmental Health)
Hernandez-Pacheco, Natalia (Centro de Investigación Biomédica en Red de Enfermedades Respiratorias)
Perez-Garcia, Javier (Universidad de La Laguna. Departamento de Bioquímica, Microbiología, Biología Celular y Genética)
Martin-Gonzalez, Elena (Universidad de La Laguna. Departamento de Bioquímica, Microbiología, Biología Celular y Genética)
Lorenzo-Diaz, Fabian (Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias. Universidad de La Laguna)
Hashimoto, Simone (Department of Respiratory Medicine. Amsterdam University Medical Center. University of Amsterdam)
Brinkman, Paul (Department of Respiratory Medicine. Amsterdam University Medical Center. University of Amsterdam)
Jorgensen, Andrea L. (Department of Health Data Science. Institute of Population Health. University of Liverpool)
Yan, Qi (Department of Obstetrics and Gynecology. Columbia University Irving Medical Center)
Forno, Erick (Division of Pediatric Pulmonary Medicine. UPMC Children's Hospital of Pittsburgh. University of Pittsburgh)
Vijverberg, Susanne J. (Department of Paediatric Respiratory Medicine and Allergy. Emma's Children Hospital. Amsterdam UMC. University of Amsterdam)
Lethem, Ryan (MRC Integrative Epidemiology Unit (IEU). Population Health Sciences. Bristol Medical School. University of Bristol)
Espuela-Ortiz, Antonio (Universidad de La Laguna. Departamento de Bioquímica, Microbiología, Biología Celular y Genética)
Gorenjak, Mario (Center for Human Molecular Genetics and Pharmacogenomics. Faculty of Medicine. University of Maribor)
Eng, Celeste (Department of Medicine. University of California San Francisco)
González-Pérez, Ruperto (Hospital Universitario de Canarias (La Laguna))
Hernández-Pérez, José M. (Hospital General de La Palma. Servicio de Neumología)
Poza-Guedes, Paloma (Hospital Universitario de Canarias. Unidad de Asma Grave. Servicio de Alergología)
Sardón, Olaia (Universidad del País Vasco. Departamento de Pediatría)
Corcuera, Paula (Hospital Universitario Donostia. Division of Pediatric Respiratory Medicine)
Hawkins, Greg A. (Department of Biochemistry. Wake Forest School of Medicine)
Marsico, Annalisa (Computational Health Center. Helmholtz Zentrum München. German Research Center for Environmental Health)
Bahmer, Thomas (Airway Research Center North (ARCN). Members of the Germany Center for Lung Research (DZL))
Rabe, Klaus F. (Airway Research Center North (ARCN). Members of the Germany Center for Lung Research (DZL))
Hansen, Gesine (Department of Pediatric Pneumology. Allergology and Neonatology. Hannover Medical School)
Kopp, Matthias V. (Department of Paediatric Respiratory Medicine. Inselspital. University Children's Hospital of Bern. University of Bern)
Rios, Raimon (Programa de Pós Graduação em Imunologia (PPGIm). Instituto de Ciências da Saúde. Universidade Federal da Bahia (UFBA))
Cruz, Maria Jesús (Hospital Universitari Vall d'Hebron)
González-Barcala, Francisco Javier (Complejo Hospitalario Universitario de Santiago de Compostela. Servicio de Neumología)
Olaguibel, José María (Complejo Hospitalario de Navarra)
Plaza, Vicente (Institut d'Investigació Biomèdica Sant Pau)
Quirce Gancedo, Santiago (Instituto de Investigación Sanitaria del Hospital Universitario La Paz)
Canino, Glorisa (Behavioral Sciences Research Institute. University of Puerto Rico)
Cloutier, Michelle (Department of Pediatrics. University of Connecticut)
Del Pozo, Victoria (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Rodriguez-Santana, Jose R. (Centro de Neumología Pediátrica)
Korta-Murua, Javier (Universidad del País Vasco. Departamento de Pediatría)
Villar, Jesús (Hospital Universitario de Gran Canaria Doctor Negrín. Multidisciplinary Organ Dysfunction Evaluation Research Network. Research Unit)
Potočnik, Uros (Laboratory for Biochemistry. Molecular Biology and Genomics. Faculty for Chemistry and Chemical Engineering. University of Maribor)
Figueiredo, Camila (Instituto de Ciências da Saúde. Universidade Federal da Bahia)
Kabesch, Michael (Department of Paediatric Pneumology and Allergy. University Children's Hospital Regensburg (KUNO))
Mukhopadhyay, Somnath (Population Pharmacogenetics Group. Biomedical Research Institute. Ninewells Hospital and Medical School. University of Dundee)
Pirmohamed, Munir (Department of Pharmacology and Therapeutics. Institute of Systems. Molecular and Integrative Biology. University of Liverpool)
Hawcutt, Daniel (NIHR Alder Hey Clinical Research Facility. Alder Hey Children's Hospital)
Melén, Erik (Sachs' Children's Hospital. South General Hospital)
Palmer, Colin (Population Pharmacogenetics Group. Biomedical Research Institute. Ninewells Hospital and Medical School. University of Dundee)
Turner, Steve (Child Health. University of Aberdeen)
Maitland-van der Zee, Anke H. (Department of Paediatric Respiratory Medicine and Allergy. Emma's Children Hospital. Amsterdam UMC. University of Amsterdam)
von Mutius, Erika (Comprehensive Pneumology Center Munich (CPC-M). Member of the German Center for Lung Research)
Celedón, Juan C. (Division of Pediatric Pulmonary Medicine. UPMC Children's Hospital of Pittsburgh. University of Pittsburgh)
Brusselle, Guy (Department of Respiratory Medicine. Erasmus University Medical Center)
Chew, Fook Tim (Department of Biological Sciences. National University of Singapore)
Bleecker, Eugene (Division of Genetics. Genomics. and Precision Medicine. Department of Internal Medicine. University of Arizona College of Medicine)
Meyers, Deborah (Division of Genetics. Genomics. and Precision Medicine. Department of Internal Medicine. University of Arizona College of Medicine)
Burchard, Esteban G. (Department of Bioengineering and Therapeutic Sciences. University of California San Francisco)
Pino-Yanes, Maria (Universidad de la Laguna. Instituto de Tecnologías Biomédicas)

Data:	2022
Resum:	Background: 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 × 10) 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 (OR) = 0. 82, p = 9. 05 × 10 and replication: OR = 0. 89, p = 5. 35 × 10) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: OR = 0. 85, p = 3. 10 × 10 and replication: OR = 0. 89, p = 1. 30 × 10). 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.
Ajuts:	Agencia Estatal de Investigación RYC-2015-17205 European Commission SAF2017-83417R Ministerio de Ciencia e Innovación PID2020-116274RB-I00 Ministerio de Ciencia e Innovación SAF2017-87417R Instituto de Salud Carlos III PT17/0019 Instituto de Salud Carlos III CB/06/06/1088 European Commission 083837 Ministerio de Ciencia, Innovación y Universidades FPU19/02175
Nota:	Altres ajuts: European Regional Development Fund "ERDF A way of making Europe"; Allergopharma-EAACI award 2021; SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020; Sandler Family Foundation; American Asthma Foundation; RWJF Amos Medical Faculty Development Program; National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL141992, R01HL141845); National Institute of Health and Environmental Health Sciences (R01ES015794, R21ES24844); National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443, R56MD013312); National Institute of General Medical Sciences (NIGMS) (RL5GM118984); Tobacco-Related Disease Research Program (24RT-0025, 27IR-0030); National Human Genome Research Institute (NHGRI) (U01HG009080); GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences; Slovenian Research Agency (P3-0067); SysPharmPediA grant, co-financed by the Ministry of Education, Science and Sport Slovenia (MIZS) (C3330-16-500106); NHS Research Scotland; Wellcome Trust Biomedical Resource (099177/Z/12/Z); Genotyping National Centre (CeGEN) CeGen-PRB3-ISCIII (AC15/00015); UK Medical Research Council and Wellcome (102215/2/13/2); University of Bristol; Swedish Heart-Lung Foundation, Swedish Research Council; Region Stockholm (ALF project and database maintenance); NHS Chair of Pharmacogenetics via the UK Department of Health; Innovative Medicines Initiative (IMI) (115010); European Federation of Pharmaceutical Industries and Associations (EFPIA); Spanish National Cancer Research Centre; Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC19/17); Erasmus Medical Center; Erasmus University Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF); U.S. National Institutes of Health (HL07966); European Social Fund "ESF Investing in your future"; Ministerio de Ciencia, Innovación y Universidades; Universidad de La Laguna (ULL); European Academy of Allergy and Clinical Immunology (EAACI); European Respiratory Society (ERS) (LTRF202101-00861); Ministry of Education, Science and Sport of the Republic of Slovenia (C3330-19-252012); Singapore Ministry of Education Academic Research Fund; Singapore Immunology Network (SIgN); National Medical Research Council (NMRC Singapore); Biomedical Research Council (BMRC Singapore); Agency for Science Technology and Research (A*STAR Singapore, 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, H17/01/a0/008); Sime Darby Technology Centre; First Resources Ltd; Genting Plantation; Olam International; U.S. National Institutes of Health (HL138098).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Asthma exacerbations ; EXTL2 ; GWAS ; PANK1 ; Single-nucleotide polymorphism
Publicat a:	Pediatric Allergy and Immunology, Vol. 33 Núm. 6 (june 2022) , p. e13802, ISSN 1399-3038

DOI: 10.1111/pai.13802
PMID: 35754128

17 p, 1.5 MB

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