Genetic associations with viral respiratory illnesses and asthma control in children.

BACKGROUND: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. OBJECTIVE: We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season. METHODS: The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma (COAST) birth cohort study. RESULTS: A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study. CONCLUSIONS: We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma.

Specific patterns of allergic sensitization in early childhood and asthma & rhinitis risk.

BACKGROUND: Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk. OBJECTIVE: To define relationships among established sensitization to particular aeroallergens, quantitative analyses of allergen-specific IgE levels, pet exposure and sensitization, and asthma and rhinitis risk. METHODS: Children at high-risk for the development of asthma and allergic diseases were enrolled at birth into the Childhood Origins of ASThma (COAST) study. Allergen-specific IgE was assessed at ages 1, 3, 6, and 9 years by fluoroenzyme immunoassay (Unicap(®) 100; Pharmacia Diagnostics). Current asthma and rhinitis were diagnosed at age 6 and 8 years. RESULTS: Sensitization to dog was strongly associated with increased asthma risk (P < 0.0001). Sensitization to perennial compared with seasonal allergens was more strongly associated with asthma risk, while sensitization to seasonal allergens was more closely associated with rhinitis risk. Increased levels of specific IgE to perennial allergens were associated with an increased asthma risk (P = 0.05), while any detectable level of IgE to seasonal allergens was associated with increased rhinitis risk (P = 0.0009). While dog and cat sensitization were both independently associated with increased asthma and rhinitis risk, dog exposure at birth was associated with a reduced risk of asthma, regardless of dog sensitization status during the first 6 years of life (P = 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Analysing specific patterns of an individual's allergic sensitization profile reveals additional relevant associations with asthma and rhinitis risk as opposed to the information gained from characterizing an individual as 'atopic' by the presence of any demonstrable sensitization alone. Furthermore, protective mechanisms of dog exposure with regards to asthma risk appear to be unrelated to the prevention of sensitization.

The influence of processing factors and non-atopy-related maternal and neonate characteristics on yield and cytokine responses of cord blood mononuclear cells.

RATIONALE: Several studies have evaluated the associations between cord blood cellular responses and atopic diseases in children, but the results of these studies are inconsistent. Variations in blood processing factors and maternal and infant characteristics are typically not accounted for and may contribute to these inconsistencies. METHODS: Cord blood samples were obtained from 287 subjects participating in the Childhood Origins of ASThma project, a prospective study of children at high risk for the development of asthma/allergies. Mononuclear cells were stimulated with phytohaemagglutinin (PHA), phorbal myristate acetate/ionomycin or a suspension of killed staphylococcus, and IFN-gamma, IL-10 and IL-13 were quantitated by ELISA. Cell yields and cytokine production were related to processing factors and maternal and infant characteristics. RESULTS: The strongest relationships between independent variables and cell yield or cytokine responses occurred with the season of birth. The highest median cell yields were seen in fall, and the lowest in summer (difference of 47%, P=0.0027). Furthermore, PHA-induced IL-5 and IL-13 responses were approximately 50% higher in spring and summer than in fall or winter (P<0.0001). Clots in the cord blood samples were associated with a reduced median cell yield (42% reduction, P<0.0001), and an increased PHA-induced IL-10 secretion (27% increase, P=0.004). CONCLUSIONS: These data suggest that season of collection, and to a lesser extent clotting in samples, affect cord blood mononuclear cell yield and cytokine responses. Careful documentation and analysis of processing and environmental variables are important in understanding biological relationships with cytokine responses, and also lead to greater comparability among studies using these techniques.