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BACKGROUND: The pathophysiological basis to severe RSV bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in disease pathogenesis. A recent twin-study estimated a heritable contribution of 22% to RSV bronchiolitis. Genetic epidemiology provides a new approach in identifying important immune determinants of disease severity. METHODS: We perform a comprehensive high density gene-region association study for severe RSV bronchiolitis in infancy at 5q31, across 11 genes including the Th2-cytokine cluster. We apply a haplotype-tagging approach to analyse genetic variation at 113 SNPs. We use 780 independent cases and 1045 controls, with sufficient power to detect small effects, perform extensive haplotype analysis, and analyse both a principal phenotype and a refined age-limited phenotype, enriched for first-exposure RSV infection. RESULTS: We find SNP associations at IL4 and identify a highly significant risk-haplotype across IL13 CNS-1 and IL4 (OR 1.69, p=0.0005), present in both case-control and family-based analysis. All associations are strongest for a phenotype limited to under 6 months of age, implicating this locus in primary RSV disease. We have previously shown the same risk-haplotype to be associated with increased IL13 expression. CONCLUSIONS: We find that a haplotype at IL13-1L4, which is associated with increased IL13 production, confers increased risk of severe primary RSV bronchiolitis in early infancy. Our study, together with previous studies implicating the same locus in atopic sensitization, suggests that primary RSV bronchiolitis and atopy share a genetic contribution at the IL13-IL4 locus.


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