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J Allergy Clin Immunol. 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.

Author information

1
Department of Public Health Sciences, Henry Ford Health System, Detroit, Mich.
2
Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, Mich.
3
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
4
School of Nursing, University of Michigan, Ann Arbor, Mich.
5
Lung Biology Center and Functional Genomics Core, University of California San Francisco, San Francisco, Calif.
6
Department of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, Calif; Department of Medicine, University of California San Francisco, San Francisco, Calif.
7
Cardiovascular Research Institute, University of California San Francisco, San Francisco, Calif; Department of Dermatology, University of California San Francisco, San Francisco, Calif.
8
Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Tenerife, Spain.
9
Lung Biology Center and Functional Genomics Core, University of California San Francisco, San Francisco, Calif; Department of Medicine, University of California San Francisco, San Francisco, Calif.
10
Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, Mich; Department of Internal Medicine, Henry Ford Health System, Detroit, Mich.
11
Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, Mich; Department of Internal Medicine, Henry Ford Health System, Detroit, Mich. Electronic address: kwillia5@hfhs.org.

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

PMID:
30367910
PMCID:
PMC6482107
[Available on 2020-05-01]
DOI:
10.1016/j.jaci.2018.09.034

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