Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma

Ahmed Edris, Emmely W. de Roos, Michael J. McGeachie, Katia M.C. Verhamme, Guy G. Brusselle, Kelan G. Tantisira, Carlos Iribarren, Meng Lu, Ann Chen Wu, Bruno H. Stricker, Lies Lahousse*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. Objective: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. Methods: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population–based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. Results: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. Conclusion: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.

Original languageEnglish
Pages (from-to)33-45
Number of pages13
JournalClinical and Experimental Allergy
Issue number1
Early online date11 Jan 2021
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
The authors have no conflict of interests to disclose. Outside of the scope of this study, KGT has received funding for work in asthma pharmacogenomics from the US National Institutes of Health, but the NIH does not stand to gain or lose financially from the results or conclusions of this article. Katia Verhamme works for a research department that receives/received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis, GSK, UCB, Amgen and Chiesi, none of which are related to the content of this work. G. Brusselle has, within the last 5 years, received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Teva; he is a member of advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi/Regeneron and Teva. LL reports Society awards sponsored by AstraZeneca and Chiesi and expert consultation for Boehringer Ingelheim GmbH and Novartis, outside the submitted work.

Funding Information:
AE has received a fellowship by the European Respiratory Society (LTRF 201801-00302). This work was partly funded by the National Institutes of Health (NIH) grants R01 NR013391, R01 HL127332, U01 HL65899 and R01 HD085993. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Outside the submitted work, Dr. Wu reports funding from?GlaxoSmithKline. We would like to thank the participants in both the Rotterdam study and the GERA study for making this scientific research possible.

Publisher Copyright:
© 2021 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.


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