Abstract
Rationale Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.
Methods A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 European-descent children treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.
Results Ten independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10−6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078, p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.
Conclusions The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Matson has nothing to disclose.
Conflict of interest: Ms. Hernandez-Pacheco reports grants from Instituto de Salud Carlos III (ISCIII) and co-funded by the European Social Funds from the European Union (ESF) “ESF invests in your future”, during the conduct of the study.
Conflict of interest: Dr. Vijverberg has nothing to disclose.
Conflict of interest: Ms. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation, and Universities (PRE2018-083837), during the conduct of the study.
Conflict of interest: Dr. Li has nothing to disclose.
Conflict of interest: Dr. Sio has nothing to disclose.
Conflict of interest: Dr. Granell has nothing to disclose.
Conflict of interest: Ms. Corrales has nothing to disclose.
Conflict of interest: Dr. Maroteau has nothing to disclose.
Conflict of interest: Dr. Lethem has nothing to disclose.
Conflict of interest: Mr. Perez-Garcia has nothing to disclose.
Conflict of interest: Dr. Farzan has nothing to disclose.
Conflict of interest: Dr. Repnik has nothing to disclose.
Conflict of interest: Dr. Gorenjak has nothing to disclose.
Conflict of interest: Dr. Soares has nothing to disclose.
Conflict of interest: Dr. Karimi has nothing to disclose.
Conflict of interest: Dr. Schieck has nothing to disclose.
Conflict of interest: Dr. Perez-Mendez has nothing to disclose.
Conflict of interest: Dr. Berce has nothing to disclose.
Conflict of interest: Dr. Tavendale has nothing to disclose.
Conflict of interest: Ms. Eng has nothing to disclose.
Conflict of interest: Dr. Sardon has nothing to disclose.
Conflict of interest: Dr. Kull has nothing to disclose.
Conflict of interest: Dr. Mukhopadhyay reports grants from The Gannochy Trust, grants from Perth and Kinross City Council, grants from Scottish Enterprises Tayside, during the conduct of the study;.
Conflict of interest: Dr. Pirmohamed reports grants from UK Department of Health, grants from UK Medical Research Council, during the conduct of the study; grants from MRC Clinical Pharmacology Training Scheme (joint funding by MRC and Roche, UCB, Eli Lilly and Novartis), grants from Joint PhD studentship funded by EPSRC and Astra Zeneca, grants from Bristol Myers Squibb, outside the submitted work;.
Conflict of interest: Dr. Verhamme reports grants from ZonMw, during the conduct of the study; and Katia Verhamme works for a department who in the past received unconditional research grants from:
Conflict of interest: Dr. Burchard reports grants from the National Heart, Lung, and Blood Institute (NHLBI) of the United States National Institutes of Health (NIH) (X01HL134589, X01HL134589,R01HL128439, R01HL135156, R01HL141992 & R01HL141845), grants from the National Institute of Environmental Health Sciences (NIEHS) (R01ES015794 & R21ES24844), grants from the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443 & R56MD013312), grants from the National Institute of General Medical Sciences (NIGMS) (RL5GM118984), other from the Tobacco-Related Disease Research Program (Award Numbers 24RT-0025 & 27IR-0030), grants from the National Human Genome Research Institute (NHGRI) (U01HG009080), grants from the Sandler Family Foundation, grants from the American Asthma Foundation, grants from the Amos Medical Faculty Development Program from the Robert Wood Johnson Foundation, grants from the Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, during the conduct of the study;.
Conflict of interest: Dr. Kabesch reports grants from European Union, German Ministry of Education and Research, German Research Foundation, during the conduct of the study; personal fees from Bionorica, Sanofi, Novartis, Bencard, outside the submitted work; personal fees from ERS, EAACI, ATS, Novartis, Glaxo, Nutricia, Hipp, Allergopharma, outside the submitted work;.
Conflict of interest: Dr. Hawcutt has nothing to disclose.
Conflict of interest: Dr. Melén has nothing to disclose.
Conflict of interest: Dr. Potocnik reports grants from Slovenian Research Agency, grants from Ministry of Education, Science and Sport Slovenia (MIZS), during the conduct of the study;.
Conflict of interest: Dr. Chew reports grants from Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network, National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore), during the conduct of the study; and consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work.
Conflict of interest: Dr. Tantisira reports grants from U.S. National Institutes of Health, during the conduct of the study;.
Conflict of interest: Dr. Turner has nothing to disclose.
Conflict of interest: Dr. Palmer has nothing to disclose.
Conflict of interest: Dr. Flores has nothing to disclose.
Conflict of interest: Dr. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry and Competitiveness, grants from Instituto de Salud Carlos III (ISCIII), during the conduct of the study;.
Conflict of interest: Dr. Maitland-van der Zee reports grants from GSK, from null, during the conduct of the study; grants from Boehringer Ingelheim, personal fees from Astra Zeneca, and Boehringer Ingelheim, outside the submitted work;.
This is a PDF-only article. Please click on the PDF link above to read it.
- Received February 17, 2020.
- Accepted November 9, 2020.
- Copyright ©ERS 2020