Asthma exacerbations are a major cause of morbidity and medical cost. In order to investigate the genetic and genomic factors that influence asthma control on steroid medication, performed genome-wide scan of single nucleotide polymorphism and meta analysis of acute asthma exacerbation in two pediatric clinical trials: Childhood Asthma Management Program (CAMP, n=581) and Childhood Asthma Research and Education (CARE, n=205) network trials.
A locus in CTNNA3 reached genome-wide significance (rs7915695, p=2.19*10-8, mean exacerbations 6.05 for minor alleles vs. 3.71 for homozygous major). Among four top SNPs replicated in BioVU, rs993312 in SEMA3D was significant (p=0.0083), and displayed stronger association among African Americans (p=0.0004 in BioVU, mean exacerbations 3.91 vs. 1.53; p=0.0089 in CAMP, mean exacerbations 6.0 vs. 3.25). CTNNA3variants did not replicate in BioVU. A regulatory variant in the CTNNA3 locus was associated with CTNNA3 mRNA expression in CD4+ cells from asthmatics (p=0.00079). CTNNA3 appears to be active in immune response, and SEMA3D has a plausible role in airway remodeling. We were also able to provide a replication of a previous association of P2RX7 with asthma exacerbation. In conclusion, we identified two loci associated with exacerbations through GWAS. CTNNA3 met genome-wide significance thresholds and SEMA3D replicated in a clinical Biobank database.
CAMP and CARE are both trials of inhaled corticosteroids for asthma management in children. Acute asthma exacerbations was defined as treatment with a five-day course of oral steroids. We obtained a replication cohort from BioVU (n=786), the Vanderbilt University electronic medical record-linked DNA biobank. We used CD4+ lymphocyte genome-wide mRNA expression profiling to identify associations of top SNPs with mRNA abundance of nearby genes. The combination of these trials provided an opportunity to identify genetic variants that may be associated with asthma exacerbation in children and uncover additional biology related to acute asthma episodes, while providing a replication in a more diverse outpatient sample.