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Summary: Background: Understanding of adolescent-onset asthma remains limited. We sought to characterise this state and identify associated factors within a longitudinal birth cohort study. Methods: The Isle of Wight Whole Population Birth Cohort was recruited in 1989 (N =1456) and characterised at 1, 2, 4, 10 and 18-years. “Adolescent-onset asthma” was defined as asthma at age 18 without prior history of asthma, “persistent-adolescent asthma” as asthma at both 10 and 18 and “never-asthma” as those without asthma at any assessment. Results: Adolescent-onset asthma accounted for 28.3% of asthma at 18-years and was of similar severity to persistent-adolescent asthma. Adolescent-onset asthmatics showed elevated bronchial hyper-responsiveness (BHR) and atopy at 10 and 18 years. BHR in this group at 10 was intermediate to that of never-asthmatics and persistent-adolescent asthma. By 18 their BHR, bronchodilator reversibility and sputum eosinophilia was greater than never-asthmatics and comparable to persistent-adolescent asthma. At 10, males who later developed adolescent-onset asthma had reduced FEV1 and FEF25–75, while females had normal lung function but then developed impaired FEV1 and FEF25–75 in parallel with adolescent asthma. Factors independently associated with adolescent-onset asthma included atopy at 10 (OR=2.35; 95% CI=1.08–5.09), BHR at 10 (3.42; 1.55–7.59), rhinitis at 10 (2.35; 1.11–5.01) and paracetamol use at 18-years (1.10; 1.01–1.19). Conclusions: Adolescent-onset asthma is associated with significant morbidity. Predisposing factors are atopy, rhinitis and BHR at age 10 while adolescent paracetamol use is also associated with this state. Awareness of potentially modifiable influences may offer avenues for mitigating this disease state. [ABSTRACT FROM AUTHOR]

Background: GATA3 activates transcription of the TH2 cytokines, including IL13, an important step in the allergic inflammatory pathway. Objective: We sought to identify associations of single nucleotide polymorphisms of the genes GATA3 and IL13 and their interactions with rhinitis and allergic sensitization during childhood. Methods: We performed genetic association studies in a cohort of children (n = 923) who have been evaluated for the development of rhinitis and allergic sensitization by means of skin prick tests (SPTs) at age 10 years. Pyrosequencing was used to genotype 7 polymorphisms from GATA3 and 5 from IL13. A novel model-selection procedure combining logistic regression models and classification was used to study the contributions of the polymorphisms and their interactions. Results: Combinations of polymorphisms and their interactions increase the risk for rhinitis and allergic sensitization at age 10 years. A model with rs1058240, rs379568, and rs4143094 (GATA3) and rs1800925 (IL13) and their interactions was selected to predict rhinitis and positive SPT responses. rs1058240 was associated with rhinitis and allergic rhinitis (P < .05), and the gene-gene interaction rs1058240:rs1800925 was associated with rhinitis (P = .043). The odds ratios for 4 genotype combinations were significant for rhinitis or SPTs (P < .044). Conclusion: Gene-gene interaction between GATA3 and IL13 polymorphisms can influence the risk of childhood rhinitis. Our study suggests that set associations of polymorphisms are important in studying genetic associations for complex phenotypes, such as rhinitis and atopy. [Copyright &y& Elsevier]

Background Filaggrin is an epidermal protein that has a role in skin barrier function. Filaggrin loss-of-function ( FLG -LOF) mutations are a significant risk factor for eczema and atopy, but their association with food allergy (FA) is less clear. Objective We explored the longitudinal relationship between 3 common FLG -LOF mutations and FA using the Isle of Wight birth cohort. Methods FA diagnosis was based on recognized allergic reactions within 4 hours after exposure to known food allergens. Food allergen sensitization (FAS) was identified by using skin prick tests conducted between 1 and 18 years of age to a range of food allergens. Three FLG mutations were genotyped in 1150 (79%) of 1456 children. The temporal relationships between FA, FAS, and eczema in children with FLG mutations were explored by using path analysis with total, direct, and indirect effect models. Results There was a significant total effect of FLG- LOF mutations on the risk of FA in later childhood at the ages of 10 (odds ratio, 31.46; 95% CI, 2.86 to >100) and 18 (odds ratio, 4.25; 95% CI, 1.55-11.61) years. Path analysis showed that there was no direct effect of FLG -LOF mutations on FA at any age; however, an indirect effect was found on FA at all ages through eczema and FAS in the earlier years. Conclusion FLG -LOF mutations are associated with FA in older children through eczema and FAS during early childhood. Our results highlight a biologically plausible pathway, which suggests that skin barrier function is important in the development and persistence of FA. [ABSTRACT FROM AUTHOR]

Background: The parent-of-origin effect is important in understanding the genetic basis of childhood allergic diseases and improving our ability to identify high-risk children. Objective: We sought to investigate the parent-of-origin effect in childhood allergic diseases. Methods: The Isle of Wight Birth Cohort (n = 1456) has been examined at 1, 2, 4, 10, and 18 years of age. Information on the prevalence of asthma, eczema, rhinitis, and environmental factors was obtained by using validated questionnaires. Skin prick tests were carried out at ages 4, 10, and 18 years, and total IgE measurement was carried out at 10 and 18 years. Parental history of allergic disease was assessed soon after the birth of the child, when maternal IgE levels were also measured. Prevalence ratios (PRs) and their 95% CIs were estimated, applying log-linear models adjusted for confounding variables. Results: When stratified for sex of the child, maternal asthma was associated with asthma in girls (PR, 1.91; 95% CI, 1.34-2.72; P = .0003) but not in boys (PR, 1.29; 95% CI, 0.85-1.96; P = .23), whereas paternal asthma was associated with asthma in boys (PR, 1.99; 95% CI, 1.42-2.79; P < .0001) but not in girls (PR, 1.03; 95% CI, 0.59-1.80; P = .92). Maternal eczema increased the risk of eczema in girls (PR, 1.92; 95% CI, 1.37-2.68; P = .0001) only, whereas paternal eczema did the same for boys (PR, 2.07; 95% CI, 1.32-3.25; P = .002). Similar trends were observed when the effect of maternal and paternal allergic disease was assessed for childhood atopy and when maternal total IgE levels were related to total IgE levels in children at ages 10 and 18 years. Conclusions: The current study indicates a sex-dependent association of parental allergic conditions with childhood allergies, with maternal allergy increasing the risk in girls and paternal allergy increasing the risk in boys. This has implications for childhood allergy prediction and prevention. [ABSTRACT FROM AUTHOR]

Background: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification. Objective: We sought to identify asthma susceptibility genes in children. Methods: A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls. Results: Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 × 10−5 to 2.2 × 10−8). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations (P = .045-.0009). ATPAF1 total RNA expression was significantly (P < .01) higher in bronchial biopsies from asthmatic patients than from controls. Conclusion: Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma. [ABSTRACT FROM AUTHOR]