Integrative approach identifies corticosteroid response variant in diverse populations with asthma

Publication date: Available online 24 October 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Albert M. Levin, Hongsheng Gui, Natalia Hernandez-Pacheco, Mao Yang, Shujie Xiao, James J. Yang, Samantha Hochstadt, Andrea J. Barczak, Walter L. Eckalbar, Dean Rynkowski, Lesly-Anne Samedy, Pui-Yan Kwok, Maria Pino-Yanes, David J. Erle, David E. Lanfear, Esteban G. Burchard, L. Keoki Williams

Abstract

Background

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

Objective

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 (i.e., the combined effect of the SNP and SNP x ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in three additional groups – African Americans (n=803 and n=563) and Latinos (n=1,461). RNA-seq data from 408 asthma cases and 405 controls 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=7.79x10^-8) and was jointly associated with asthma exacerbations in three validation cohorts (P=0.023, P=0.029, and P=0.041). RNA-seq analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P=6.10x10-4). RNASE2 encodes eosinophil-derived neurotoxin (EDN), and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (i.e., high pre-treatment EDN levels or blood eosinophil counts).

Conclusion

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

Clinical Implications

African Americans and Latinos are disproportionately affected by asthma and its complications. Here we identify a pharmacogenomic variant that may assist in identifying individuals from these groups who will respond to ICS treatment.

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