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Abstract
Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11–1.25), Pdiscovery = 2.6 × 10−9) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
Highlights
Asthma with severe exacerbation is the most common cause of hospitalization among young children
Based on gene expression data from nasal epithelium cells (NECs) obtained from the COPSAC2010 cohort (357 children), we examined the presence of expression quantitative trait loci signals for the FUT2/MAMSTR top SNP, rs281379
Based on the known biological function of FUT2 for the secretion of A and B antigens on epithelial surfaces, including airway epithelium, we looked for evidence of an association between the ABO locus on chromosome 9 and childhood asthma with severe exacerbations
Summary
Asthma with severe exacerbation is the most common cause of hospitalization among young children. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis. One specific subtype is likely to be closely linked to a specific disease mechanism and might allow detection of subtype-specific susceptibility loci as previously demonstrated in a GWAS of early childhood asthma with severe exacerbations[10] Another potential explanation for the missing heritability is the interaction between genetic variants, so-called epistasis, only a few examples of this have been demonstrated in human studies[15,16]. We explore potential underlying mechanisms using prospective clinical studies with information on infectious triggers of acute respiratory illnesses
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