Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood

Background Genetic heterogeneity in type I interferon related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. Methods In two prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until one and two years of age, respectively. At age 3 months, whole blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. Results In the STEPS Study (n=1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio [aIRR], 0.77 [95% CI, 0.61-0.96] for rs273259 and 0.74 [0.55-0.99] for rs1333969) and courses of antibiotics for RTIs (aIRR, 0.76 [0.62-0.95] and 0.73 [0.56-0.97], respectively. In the FinnBrain cohort (n=971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other interferon related genes. Conclusions Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated interferon pathway activation by respiratory viruses.