Integrative approach identifies corticosteroid response variant in diverse populations with asthma

J Allergy Clin Immunol. 2019 May;143(5):1791-1802. doi: 10.1016/j.jaci.2018.09.034. Epub 2018 Oct 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Cortex Hormones / therapeutic use*
  • Adult
  • Asthma / drug therapy*
  • Asthma / epidemiology
  • Asthma / genetics
  • Black or African American*
  • Child
  • Cohort Studies
  • Disease Progression
  • Eosinophil-Derived Neurotoxin / genetics*
  • Eosinophils / immunology*
  • Genome-Wide Association Study
  • Genotype*
  • Hispanic or Latino*
  • Humans
  • Leukocyte Count
  • Male
  • Metered Dose Inhalers
  • Middle Aged
  • Pharmacogenomic Variants
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Treatment Outcome
  • United States / epidemiology
  • Young Adult

Substances

  • Adrenal Cortex Hormones
  • Eosinophil-Derived Neurotoxin
  • RNASE2 protein, human