Johanna Lempainen1,2,3, Laura S Korhonen1,4, Katri Kantojärvi4,5,6, Santtu Heinonen7, Laura Toivonen1, Panu Räty4, Octavio Ramilo8, Asuncion Mejias8, Antti-Pekka Laine2, Tytti Vuorinen9, Matti Waris9, Linnea Karlsson4,10,11, Hasse Karlsson4,10,12, Tiina Paunio4,5,6, Ville Peltola1. 1. Department of Paediatrics and Adolescent Medicine, University of Turku and Turku University Hospital, Turku, Finland. 2. Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. 3. Clinical Microbiology, Turku University Hospital, Turku, Finland. 4. FinnBrain Birth Cohort Study, Turku Brain and Mind Center, Department of Clinical Medicine, University of Turku, Turku, Finland. 5. Finnish Institute for Health and Welfare, Genomics and Biobank Unit, Helsinki, Finland. 6. Department of Psychiatry and SleepWell Research Program, Faculty of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 7. New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 8. Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA. 9. Institute of Biomedicine, University of Turku and Department of Clinical Microbiology, Turku University Hospital, Turku, Finland. 10. Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland. 11. Department of Child Psychiatry, University of Turku and Turku University Hospital, Turku, Finland. 12. Department of Psychiatry, University of Turku and Turku University Hospital, Turku, Finland.
Abstract
BACKGROUND: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. METHODS: In 2 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 1 or 2 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, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.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 IFN-related genes. CONCLUSIONS: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.
BACKGROUND: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. METHODS: In 2 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 1 or 2 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, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.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 IFN-related genes. CONCLUSIONS: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.
Authors: Leigh M Howard; Yuhan Liu; Yuwei Zhu; Dandan Liu; John V Willams; Ana I Gil; Marie R Griffin; Kathryn M Edwards; Claudio F Lanata; Carlos G Grijalva Journal: J Infect Dis Date: 2022-01-05 Impact factor: 7.759