Integrative approach identifies corticosteroid response variant in diverse populations with asthma

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=7.79×10 −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=6.10×10 −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.

Advances in asthma and allergic disease genetics: Is bigger always better?

“…No genome-wide significant loci were identified, but a locus near APOBEC3B and APO-BEC3C on chromosome 22q13.1 was suggestively significant and replicated in a meta-analysis of studies conducted on Europeans. 44 In the second study, Levin et al 45 assessed corticosteroid responsiveness in 244 African American subjects 12 years of age and older who were monitored while receiving inhaled corticosteroid therapy. Two variants surpassed the genome-wide significant threshold.…”

<p>Pharmacogenetics of Pediatric Asthma: Current Perspectives</p>

“…Altogether, eleven candidate-gene studies, [24][25][26][27][28][55][56][57][58][59] a meta-analysis of a candidate gene, 60 and six pharmacogenomic studies (one of them in adults but including replication in children) have been performed. 32,36,40,73,74,79 During this period, candidate-gene studies reported the association of genes previously described in pharmacogenetic studies of pediatric asthma with treatment response (ADRB2, GSDMB, FCER2, and VEGFA). 13,[16][17][18] Additionally, other candidate genes have been related for the first time to this phenotype in children (SPATS2L, ASB3, IL1RL1, MMP9, and COL2A1).…”

“…62 Interestingly, a GWAS reported the association of a SNP within EDDM3B with ICS response in adults as discovery, and this finding was replicated in childhood asthma. 74 Since this gene is related to eosinophilic inflammation, 74,77,78 this feature may be common in both phenotypes and may condition treatment response to ICS in both age groups. Moreover, some of the candidate genes associated during this period with treatment response in childhood asthma had been previously reported with ICS response in asthma adult patients (COL2A1 72 ) and with bronchodilator response both in children and adults (ASB3 30 and SPAT2SL 29 ).…”

“…In 2019, two GWAS have assessed ICS response in pediatric asthma (Table 2). 73,74 Hernandez-Pacheco et al 73 presence of asthma exacerbations during the last 12 months, considering as exacerbations ER visits, hospitalizations, or the administration of OCS because of asthma. Fifteen independent SNPs were suggestively associated with ICS response (p-value≤5 × 10 −6 ) and one of them replicated in Europeans (n=1,697) at a nominal significance level (rs5995653, p-value=0.008).…”

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response

“…Remarkably, in recent years, the number of pharmacogenomic, epigenomic, and metabolomic studies that included ethnically diverse minority populations such as African Americans and Hispanic/Latinos have increased compared to the past [25][26][27]38,63,82,83]. However, studies in populations of Asian ancestry remain still scarce [51].…”