Integrative approach identifies corticosteroid response variant in diverse populations with asthma

• Published in: Journal of allergy and clinical immunology 2019-05, Vol.143 (5), p.1791-1802
• Main Authors: Levin, Albert M., Gui, Hongsheng, Hernandez-Pacheco, Natalia, Yang, Mao, Xiao, Shujie, Yang, James J., Hochstadt, Samantha, Barczak, Andrea J., Eckalbar, Walter L., Rynkowski, Dean, Samedy, Lesly-Anne, Kwok, Pui-Yan, Pino-Yanes, Maria, Erle, David J., Lanfear, David E., Burchard, Esteban G., Williams, L. Keoki
• Format: Article
• Language: English
• Subjects: Adolescent; Adrenal Cortex Hormones - therapeutic use; Adult; African Americans; Alleles; Asthma; Asthma - drug therapy; Asthma - epidemiology; Asthma - genetics; Black or African American; Child; Cohort Studies; Corticosteroids; Disease Progression; EDDM3B; Eosinophil-derived neurotoxin; Eosinophil-Derived Neurotoxin - genetics; eosinophils; Eosinophils - immunology; Ethnicity; Gene expression; Gene polymorphism; Genome-Wide Association Study; Genomes; Genotype; Hispanic or Latino; Humans; Leukocyte Count; Leukocytes (eosinophilic); Male; Metered Dose Inhalers; Middle Aged; Minority & ethnic groups; Neurotoxins; Pharmacogenetics; Pharmacogenomic Variants; Pharmacogenomics; Pharmacy; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; Pretreatment; Ribonucleic acid; RNA; RNASE2; Single-nucleotide polymorphism; Studies; transcriptome; Treatment Outcome; United States - epidemiology; Young Adult
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2018.09.034

Although inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations. We sought to identify genetic predictors of ICS response in multiple population groups with asthma. 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. 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). We identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.