Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 May;143(5):1791-1802.
doi: 10.1016/j.jaci.2018.09.034. Epub 2018 Oct 24.

Integrative approach identifies corticosteroid response variant in diverse populations with asthma

Albert M Levin  1 , Hongsheng Gui  2 , Natalia Hernandez-Pacheco  3 , Mao Yang  2 , Shujie Xiao  2 , James J Yang  4 , Samantha Hochstadt  2 , Andrea J Barczak  5 , Walter L Eckalbar  5 , Dean Rynkowski  2 , Lesly-Anne Samedy  6 , Pui-Yan Kwok  7 , Maria Pino-Yanes  8 , David J Erle  9 , David E Lanfear  10 , Esteban G Burchard  6 , L Keoki Williams  11
Affiliations

Integrative approach identifies corticosteroid response variant in diverse populations with asthma

Albert M Levin et al. J Allergy Clin Immunol. 2019 May.

Abstract

Background: Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations.

Objective: We sought to identify genetic predictors of ICS response in multiple population groups with asthma.

Methods: The discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression.

Results: One variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10-8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10-4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts).

Conclusion: We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.

Keywords: EDDM3B; Pharmacogenetics; RNASE2; eosinophil-derived neurotoxin; eosinophils; transcriptome.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: NH-P reports grant funding through a fellowship from the Instituto de Salud Carlos III. WLE reports grant funding from the NIH. MP-Y reports grant funding from the Spanish Ministry of Economy, Industry and Competitiveness and Instituto de Salud Carlos III. DJE reports grant funding from the NIAID, NIH; an honorarium and travel expenses from Boehringer Ingelheim; and consulting and travel expenses from Coherus. LKW reports grant funding from the NIDDK, NHBLI and NIAID, NIH and the American Asthma Foundation. The remaining authors have no disclosures to reports.

Figures

Figure 1.
Figure 1.
Manhattan plot of the p-values from the genome wide association analysis of inhaled corticosteroid (ICS) response in the discovery set (n=244). Each p-value represents the statistical significance of jointly testing the contribution of both the SNP and SNP x ICS interaction terms. The Bonferroni-adjusted significance level (p=8.72×10−8) is shown as a solid gray line, and a pvalue threshold of 10−5 is shown as a dashed gray line.
Figure 2.
Figure 2.
Relationship between rs3827907 genotype and absolute change in Asthma Control Test (ACT) composite score among African American participants in the SAPPHIRE cohort following 6 weeks of observed inhaled corticosteroid (ICS) treatment (n=244). Results are stratified by levels of patient ICS use (≤75% adherence was considered low use and >75% adherence was considered high use). Black lines connect the means for each group.
Figure 3.
Figure 3.
Effect of baseline measures of eosinophil-derived neurotoxin (EDN) on relationship between rs3827907 C-allele carrier status and absolute change in Asthma Control Test (ACT) composite score among African American participants in the SAPPHIRE cohort following 6 weeks of observed inhaled corticosteroid (ICS) treatment (n=243). Results are stratified by levels of patient ICS use (≤75% adherence was considered low use and >75% adherence was considered high use) and baseline serum levels of EDN. Low and high EDN levels were defined as those ≤2.34 ng/mL and >2.34 ng/mL (the median level), respectively. Black lines connect the means for each group.
Figure 4.
Figure 4.
Effect of baseline blood eosinophil counts on relationship between rs3827907 C-allele carrier status and absolute change in Asthma Control Test (ACT) composite score among African American participants in the SAPPHIRE cohort following 6 weeks of observed inhaled corticosteroid (ICS) treatment (n=113). Results are stratified by levels of patient ICS use (≤75% adherence was considered low use and >75% adherence was considered high use) and blood eosinophil counts measured before initiating ICS treatment. Low and high eosinophil counts were defined as those ≤222 cells/μL and >222 cells/ μL (the median level), respectively. Black lines connect the means for each group.
See this image and copyright information in PMC

References

    1. Akinbami LJ, Moorman JE, Bailey C, Zahran HS, King M, Johnson CA, et al. Trends in asthma prevalence, health care use, and mortality in the United States, 2001–2010. NCHS Data Brief 2012:1–8. - PubMed
    1. Sin DD, Man J, Sharpe H, Gan WQ, Man SF. Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. JAMA 2004; 292:367–76. - PubMed
    1. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343:332–6. - PubMed
    1. Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011; 365:1173–83. - PMC - PubMed
    1. Hawkins GA, Lazarus R, Smith RS, Tantisira KG, Meyers DA, Peters SP, et al. The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. J Allergy Clin Immunol 2009; 123:1376–83. - PMC - PubMed

Publication types

MeSH terms

Substances