CTNNA3 and SEMA3D: Promising loci for asthma exacerbation identified through multiple genome-wide association studies

Abstract

BACKGROUND Asthma exacerbations are a major cause of morbidity and medical cost. OBJECTIVE The objective of this study was to identify genetic predictors of exacerbations in subjects with asthma. METHODS We performed GWAS 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. 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. RESULTS 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). CTNNA3 variants 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 also provide a replication of a previous association of P2RX7 with asthma exacerbation. CONCLUSIONS We identified two loci associated with exacerbations through GWAS. CTNNA3 met genome-wide significance thresholds and SEMA3D replicated in a clinical Biobank database.

The cardiomyocyte protein αT-catenin contributes to asthma through regulating pulmonary vein inflammation

“…Our findings mechanistically support several human GWA studies linking αT-cat ( CTNNA3 ) to steroid-resistant asthma in children(3) asthmatic exacerbations in children(4), and occupational asthma in adults (13, 14). Importantly, we found that loss of αT-cat is associated with a dramatic reduction in PV inflammation in the HDM murine model of atopic asthma, suggesting that cardiomyocytes within PV may contribute to the inflammatory milieu of adjacent airways.…”

“…Remarkably, the most recent human genomic data identifying polymorphisms associated with asthma exacerbations in children(4) further support the notion of a cardiac cell/PV contribution to asthma, with αT-cat ( CTNNA3 ) as the top-hit and two other associated genes with direct and established cardiac cell/PV functions(4). These included the sarcomere structural protein, titin, which is important for the contraction of cardiac tissues(24) and the secreted vascular guidance protein, semaphorin 3d, whose primary role is in patterning and development of the PV(25).…”

“…These included the sarcomere structural protein, titin, which is important for the contraction of cardiac tissues(24) and the secreted vascular guidance protein, semaphorin 3d, whose primary role is in patterning and development of the PV(25). Thus, our evidence that the cardiomyocyte cell adhesion protein, αT-cat, is necessary for the pathogenesis of asthma in the HDM murine model, together with the unexpected observation that titin and Semaphorin 3d are also associated with asthmatic exacerbations(4), suggest that PV structures or their cardiomyocyte constituents may be an important contributor to allergic airway disease.…”

“…Indeed, our group previously found that αT-cat KO mice show altered lung mechanics, specifically in the generation of an enlarged pressure volume curve, and were more susceptible to diisocyanate asthma(9). The study that follows continues our experimental interrogation of the numerous genetic associations between αT-cat and asthma(3, 4) by determining the contribution of this cardiac junction protein to the pathogenesis of atopic asthma, which may be particularly relevant to forms of asthma resistant to steroid therapy.…”

“…Recently, a genome-wide association (GWA) study found that polymorphisms in alpha-T-catenin (αT-cat; CTNNA3 ) were associated with steroid-resistance in asthma, where children with asthma carrying the minor haplotype failed to benefit from inhaled corticosteroids(3). Additionally, an independent GWA study found that αT-cat polymorphisms were also associated with the rate of asthmatic exacerbations(4). …”