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Meta-Analysis
. 2022 Jun;33(6):e13802.
doi: 10.1111/pai.13802.

Multi-ancestry genome-wide association study of asthma exacerbations

Esther Herrera-Luis  1 , Victor E Ortega  2 , Elizabeth J Ampleford  3 , Yang Yie Sio  4 , Raquel Granell  5 , Emmely de Roos  6   7 , Natalie Terzikhan  6   7 , Ernesto Elorduy Vergara  8 , Natalia Hernandez-Pacheco  9   10 , Javier Perez-Garcia  1 , Elena Martin-Gonzalez  1 , Fabian Lorenzo-Diaz  1   11 , Simone Hashimoto  12 , Paul Brinkman  12 ; U-BIOPRED Study Group; Andrea L Jorgensen  13 , Qi Yan  14 , Erick Forno  15 , Susanne J Vijverberg  16   17   18 , Ryan Lethem  5 , Antonio Espuela-Ortiz  1 , Mario Gorenjak  19 , Celeste Eng  20 , Ruperto González-Pérez  21   22 , José M Hernández-Pérez  23   24 , Paloma Poza-Guedes  21   22 , Olaia Sardón  25   26 , Paula Corcuera  25 , Greg A Hawkins  27 , Annalisa Marsico  28 , Thomas Bahmer  29   30 , Klaus F Rabe  29   30 , Gesine Hansen  31 , Matthias Volkmar Kopp  32   33   34 , Raimon Rios  35 , Maria Jesus Cruz  10   36 , Francisco-Javier González-Barcala  37 , José María Olaguibel  10   38 , Vicente Plaza  10   39 , Santiago Quirce  10   40 , Glorisa Canino  41 , Michelle Cloutier  42 , Victoria Del Pozo  10   43 , Jose R Rodriguez-Santana  44 , Javier Korta-Murua  26 , Jesús Villar  10   45 , Uroš Potočnik  46 , Camila Figueiredo  47 , Michael Kabesch  48 , Somnath Mukhopadhyay  49   50 , Munir Pirmohamed  51 , Daniel B Hawcutt  52   53   54 , Erik Melén  9   55 , Colin N Palmer  50 , Steve Turner  56 , Anke H Maitland-van der Zee  16   17   18 , Erika von Mutius  57   58   59 , Juan C Celedón  15 , Guy Brusselle  6   7   60 , Fook Tim Chew  4 , Eugene Bleecker  61 , Deborah Meyers  61 , Esteban G Burchard  22   62 , Maria Pino-Yanes  1   10   63
Affiliations
Meta-Analysis

Multi-ancestry genome-wide association study of asthma exacerbations

Esther Herrera-Luis et al. Pediatr Allergy Immunol. 2022 Jun.

Abstract

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 × 10-5 ) 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 × 10-6 and replication: ORT allele = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10-5 and replication: ORC allele = 0.89, p = 1.30 × 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.

Keywords: EXTL2; PANK1; GWAS; asthma exacerbations; single-nucleotide polymorphism.

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Conflict of interest statement

AE‐O received grants from the Spanish Ministry of Science, Innovation, and Universities (MICIU) and Universidad de La Laguna (ULL). EH‐L, and MP‐Y report funding from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and by the European Social Fund “ESF Investing in your future” by the European Union. JP‐G reports funding from the Spanish Ministry of Universities. MP‐Y and FLD report grants from MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund “ERDF A way of making Europe” by the European Union. MP‐Y reports grant support from GlaxoSmithKline, Spain paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for a project outside the submitted work. MP‐Y and JV reports grants from Instituto de Salud Carlos III, Madrid, Spain. JV also reports funding by ISCIII and the European Regional Development Fund “ERDF A way of making Europe”. JMH‐P has received fees from CSL Behring, GSK, Astra‐Zeneca, laboratorios Menarini, Boehringer Ingelheim, FAES, laboratorios Esteve, Laboratorios Ferrer, Mundipharma, Laboratorios Rovi, Roche, Novartis, GRIFOLS, Pfizer, Acthelion‐Jansen, Chiesi y Laboratorios Bial for the realization of courses, talks, consultancies, and other activities related to his professional activity. 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). FTC 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. UP and MG received grants from the Ministry of Education, Science and Sport from Slovenia, the Slovenian Research Agency. M‐JC received grants from the Instituto de Salud Carlos III. DH received grant support from by NIHR for work on NIHR Alder Hey Clinical Research Facility, received payment for medicolegal report writing not related to asthma or pharmacogenomics for UK family court as an expert in pediatric clinical pharmacology. FJ‐B received fees from ALK, Astra‐Zeneca (AZ), Bial, Chiesi, Gebro Pharma, GlaxoSmithKline (GSK), Menarini, Rovi, Roxall, Sanofi, Stallergenes‐Greer and Teva. G‐B received fees from AZ, GSK, Boehringer‐Ingelheim, Novartis, Chiesi and Sanofi. JC received research materials from Pharmavite and GSK and Merck in order to provide medications free of cost to participants in NIH‐funded studies, unrelated to the current work. VO received grants from the National Heart, Lung, and Blood Institute, has participated in Data Safety Monitoring Boards for Regeneron and Sanofi, and participated as a Chair of the section on Genetics and Genomics of the American Thoracic Society. MVK has received grants from the German Federal Ministry of Education and Research, fees from Allergopharma GmbH, Sanofi Aventis GmbH, Infectopharm GmbH, Vertex GmbH, and Leti GmbH, has participated in Data Safety Monitoring Boards for Sanofi Aventis GmbH, and is the president of the German‐Swiss‐Austrian Society of Pediatric Pulmonology (GPP). NHP received support from the Instituto de Salud Carlos III, the European Social Funds from the European Union “ESF invests in your future,” the European Academy of Allergy and Clinical Immunology, and the European Respiratory Society. MP has received grants from NHS Chair of Pharmacogenetic grant from UK Department of Health, has received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co‐funded by MRC and Roche, UCB, Eli Lilly and Novartis); Joint PhD funding from EPSRC and AZ, and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol‐Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. MP is part of the IMI Consortium ARDAT (www.ardat.org). SQ has received fees from GSK, AZ, Sanofi, Teva, Novartis, and Chiesi. SJ‐HV has received grants from SysPharmPediA EraNet. VdP has received fees from AZ and GSK. VP has received fees from Sanofi, AZ, Chiesi, MSD, and Boehringer Ingelheim, grant support from MSD, Chiesi Institutional, and Menarini. EvM has received grants from the German Federal Ministry of Education and Research and the Bavarian State Ministry of Health and Care, royalties/licenses from Elsevier GmbH, Georg Thieme Verlag, Springer‐Verlag GmbH and Elsevier Ltd. EvM has recieved fees from the Chinese University of Hongkong, European Commission, HiPP GmbH & Co KG, AZ, Imperial College London, Massachusetts Medical Society, Springer‐Verlag GmbH, Elsevier Ltd., Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), Universiteit Utrecht, Faculteit Diergeneeskunde, Universität Salzburg, Springer Medizin Verlag GmbH, Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), Klinikum Rechts der Isar, University of Colorado, Paul‐Martini‐Stiftung, Astra Zeneca, Imperial College London, Children´s Hospital Research Institute of Manitoba, Kompetenzzentrum für Ernährung (Kern), OM Pharma S.A., Swedish Pediatric Society for Allergy and Lung Medicine, Chinese College of Allergy and Asthma (CCAA), Verein zur Förderung der Pneumologie am Krankenhaus Großhansdorf e.V., Pneumologie Developpement, Mondial Congress & Events GmbH & Co. KG, American Academy of Allergy, Asthma & Immunology, Imperial College London, Margaux Orange, Volkswagen Stiftung, Böhringer Ingelheim International GmbH, European Respiratory Society (ERS), Universiteit Utrecht, Faculteit Diergeneeskunde, Österreichische Gesellschaft f. Allergologie u. Immunologie, Massachusetts Medical Society, OM Pharma S. A., Hanson Wade Ltd., iKOMM GmbH, DSI Dansk Borneastma Center, American Thoracic Society, HiPP GmbH & Co KG, Universiteit Utrecht, Faculteit Bètawetenschappen. EvM has patents No. PCT/EP2019/085016, EP21189353.2. 2021. and PCT/US2021/016918. 2021. pending, royalties paid to ProtectImmun for patent EP2361632 and patents EP1411977, EP1637147, and EP 1964570 licensed to ProtectImmun. EvM is a member of the EXPANSE Scientific Advisory Board, Member of the BEAMS External Scientific Advisory Board (ESAB), Member of the Editorial Board of “The Journal of Allergy and Clinical Immunology: In Practice”, Member of the Scientific Advisory Board of the Children's Respiratory and Environmental Workgroup (CREW), Member of the International Scientific & Societal Advisory Board (ISSAB) of Utrecht Life Sciences (ULS), University of Utrecht, Member of External Review Panel of the Faculty of Veterinary Science, University of Utrecht, Member of the Selection Committee for the Gottfried Wilhelm Leibniz Programme (DFG), Member of the International Advisory Board of Asthma UK Centre for Applied Research (AUKCAR), Member of the International Advisory Board of “The Lancet Respiratory Medicine”, Member of the Scientific Advisory Board of the CHILD (Canadian Healthy Infant Longitudinal Development) study, McMaster University, Hamilton, Canada, Asthma UK Centre for Applied Research and the Pediatric Scientific Advisory Board Iceland. The other authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Manhattan plot of the results of the discovery stage of the multi‐ancestry meta‐analysis of GWAS of asthma exacerbations (represented as ‐log10 p‐value on the y‐axis) along the chromosome position of the variants analyzed (x‐axis). The suggestive (p = 5 × 10−5) and genome‐wide (p = 5 × 10−8) significance thresholds are indicated by the black line and dark gray lines
FIGURE 2
FIGURE 2
Forest plot of the association results for rs12091010 (VCAM1/EXTL2) in the meta‐analysis of GWAS of asthma exacerbations. ALSPAC (discovery), SCSGES (discovery), and the subset of samples from BREATHE genotyped with the Illumina Infinium CoreExome‐24 BeadChip (replication) had no genotyped or imputed data for rs12091010
FIGURE 3
FIGURE 3
Forest plot of the association results for rs943126 (PANK1) in the meta‐analysis of GWAS of asthma exacerbations. The subset of samples from BREATHE genotyped with the Illumina Infinium CoreExome‐24 BeadChip (replication) had no available genotyped or imputed data for rs943126
See this image and copyright information in PMC

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