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.
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.
Conclusions The results suggest that gestational eczema in healthy women may be predictable based on the eczema history of their mothers and the level of methylation of a CpG site in the filaggrin ...gene.
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.
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