Nasal epithelial transcriptome-wide isoform-level expression and asthma endotypes in youth

Background: Previous transcriptome-wide association studies of asthma lacked analyses of isoform expression. Objective: We sought to identify isoforms associated with asthma endotypes in children and adolescents. Methods: Meta-analysis of association between isoform- and gene-level nasal epithelial expression and TH2-high or TH17-high asthma (with TH2-low/TH17-low asthma as the reference group) in 459 youths with asthma aged 8-20 years in 3 studies: Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR), Stress and Treatment Response in Puerto Rican and African American Children With Asthma (STAR), and Vitamin D Kids Asthma (VDKA). Genes or isoforms with the same direction of association with an endotype in all cohorts and a meta-analysis false discovery rate–adjusted P < .01 were considered to have significantly differential expression. Results: In total, 6,607 isoforms encoded by 5,168 genes were associated with TH2-high asthma; 1,019 (19.7%) of these 5,168 genes were only identified in the isoform analysis, including CTNND1, CREM, TAOK2, and AIM1. A total of 4,430 isoforms encoded by 3,643 genes were associated with TH17-high asthma; 371 (10.2%) of these genes were only identified in the isoform analysis, including PSAP, FAM65B, and CFLAR. While top findings in the gene- and isoform-level analyses often overlapped, the isoforms of many genes showed differential isoform usage. In TH2-high asthma, 499 genes (encoding 731 isoforms) altered isoform usage, including CDH26, IL1RL1, MAP2K6, and SLC39A8. In TH17-high asthma, 113 genes (encoding 160 isoforms) altered isoform usage, including SBNO2, PSMB8, and NCOA7. Conclusions: An isoform-level analysis complemented a gene-level analysis of expression and identified novel genes for asthma endotypes.