FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

Abstract

AbstractAsthma 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 nearFUT2/MAMSTRon 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 inFUT2andABO. We further discover and replicate a potential causal mechanism behind this interaction related toS. pneumoniaerespiratory 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.