Bronchial Airway Inducible Expression and Methylation QTL Mapping Identifies a Single Nucleotide Polymorphism Predicting Inhaled Corticosteroids Response Heterogeneity

Objectives: We aimed to identify genetic variants affecting gene expression and methylation changes in airway wall biopsies before and after ICS and investigate whether these are associated with poor response to ICS. Methods: Quantitative Trait Locus (QTL) Mapping profiling of paired bronchial biopsies from 42 COPD patients, was performed prior to and 6 months post ICS use. The window size was 1Mb flanking gene limits and the false discovery rate was used to adjust for multiple comparisons. Association between SNPs and gene expression (eQTL) or gene methylation (meQTL) changes upon ICS use was evaluated. Subsequently, a candidate-gene study was conducted in asthma patients treated with ICS to investigate whether these SNPs are associated with ICS response. Poor ICS response was defined as presence of exacerbations despite ICS use in the last 6-12 months. Logistic regressions were used to test the association and Bonferroni correction was applied. Results: 18 eQTL and 57 meQTL SNPs were associated with ICS response. When these SNPs were tested in asthma patients (3,722 children for eQTL and 1,166 children for meQTL), the only significant variant was the meQTL SNP rs7220099, an intergenic variant at locus 17q12 with an allele frequency of 33% and a lung eQTL for TBC1 domain family member 3D. The G allele increased the risk of exacerbations (pooled OR: 1.39 95%CI 1.19-1.63, p-value = 2.4 x 10-5). Conclusions: Our results show that gene expression and methylation profiling prior and post ICS use are quite different between asthma and COPD but still may help to find functional SNPs predicting ICS response.