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Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma

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Abstract
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, rs1134481T 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.
Keywords
Immunology, Immunology and Allergy

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MLA
Edris Mohamed, Ahmed, et al. “Pharmacogenetics of Inhaled Corticosteroids and Exacerbation Risk in Adults with Asthma.” CLINICAL AND EXPERIMENTAL ALLERGY, vol. 52, no. 1, 2022, pp. 33–45, doi:10.1111/cea.13829.
APA
Edris Mohamed, A., de Roos, E., McGeachie, M. J., Verhamme, K., Brusselle, G., Tantisira, K. G., … Lahousse, L. (2022). Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma. CLINICAL AND EXPERIMENTAL ALLERGY, 52(1), 33–45. https://doi.org/10.1111/cea.13829
Chicago author-date
Edris Mohamed, Ahmed, Emmely de Roos, Michael J. McGeachie, Katia Verhamme, Guy Brusselle, Kelan G. Tantisira, Carlos Iribarren, et al. 2022. “Pharmacogenetics of Inhaled Corticosteroids and Exacerbation Risk in Adults with Asthma.” CLINICAL AND EXPERIMENTAL ALLERGY 52 (1): 33–45. https://doi.org/10.1111/cea.13829.
Chicago author-date (all authors)
Edris Mohamed, Ahmed, Emmely de Roos, Michael J. McGeachie, Katia Verhamme, Guy Brusselle, Kelan G. Tantisira, Carlos Iribarren, Meng Lu, Ann Chen Wu, Bruno H. Stricker, and Lies Lahousse. 2022. “Pharmacogenetics of Inhaled Corticosteroids and Exacerbation Risk in Adults with Asthma.” CLINICAL AND EXPERIMENTAL ALLERGY 52 (1): 33–45. doi:10.1111/cea.13829.
Vancouver
1.
Edris Mohamed A, de Roos E, McGeachie MJ, Verhamme K, Brusselle G, Tantisira KG, et al. Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma. CLINICAL AND EXPERIMENTAL ALLERGY. 2022;52(1):33–45.
IEEE
[1]
A. Edris Mohamed et al., “Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma,” CLINICAL AND EXPERIMENTAL ALLERGY, vol. 52, no. 1, pp. 33–45, 2022.
@article{8690379,
  abstract     = {{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, rs1134481T 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.}},
  author       = {{Edris Mohamed, Ahmed and de Roos, Emmely and McGeachie, Michael J. and Verhamme, Katia and Brusselle, Guy and Tantisira, Kelan G. and Iribarren, Carlos and Lu, Meng and Wu, Ann Chen and Stricker, Bruno H. and Lahousse, Lies}},
  issn         = {{0954-7894}},
  journal      = {{CLINICAL AND EXPERIMENTAL ALLERGY}},
  keywords     = {{Immunology,Immunology and Allergy}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{33--45}},
  title        = {{Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma}},
  url          = {{http://dx.doi.org/10.1111/cea.13829}},
  volume       = {{52}},
  year         = {{2022}},
}

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