Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

Elevated exhaled nitric oxide in high-risk neonates precedes transient early but not persistent wheeze.

RATIONALE: Elevated fractional exhaled nitric oxide (Fe(NO)) concentration has been suggested to predict early childhood wheeze and sensitization. OBJECTIVES: To investigate the association between Fe(NO) in asymptomatic neonates and the development of wheeze patterns and atopic intermediary phenotypes in the first 6 years of life. METHODS: We measured Fe(NO) in 253 healthy 1-month-old neonates from the Copenhagen Prospective Study on Asthma in Childhood birth cohort and monitored prospectively wheezy episodes by daily diary cards during the first 6 years of life. Total IgE, specific IgE, and blood eosinophil count were assessed at age 6 months, 4 years, and 6 years. Associations were studied by Cox regression, logistic regression, and generalized linear models. MEASUREMENTS AND MAIN RESULTS: Increased neonatal Fe(NO) level was significantly associated with the development of recurrent wheeze in the first year of life (hazard ratio, 2.63; 95% confidence interval, 1.1 to 6.2; P = 0.026) but not thereafter. The association was unaffected by environmental tobacco smoke exposure. Fe(NO) was not associated with elevated levels of total IgE, specific IgE, or blood eosinophil count at any age point and was unrelated to neonatal lung function. CONCLUSIONS: An elevated Fe(NO) level in asymptomatic neonates born to mothers with asthma preceded the development of transient early wheezing, but not persistent wheezing during preschool age, and was unrelated to atopy. This suggests an early disease process other than small airway caliber contributing to the transient wheezing phenotype.

Increased risk of eczema but reduced risk of early wheezy disorder from exclusive breast-feeding in high-risk infants.

BACKGROUND: Breast-feeding is recommended for the prevention of eczema, asthma, and allergy, particularly in high-risk families, but recent studies have raised concern that this may not protect children and may even increase the risk. However, disease risk, disease manifestation, lifestyle, and the choice to breast-feed are interrelated, and therefore, analyzing true causal effects presents a number of methodologic challenges. OBJECTIVE: First, to assess the effect from duration of exclusive breast-feeding on the development of eczema and wheezy disorders during the first 2 years of life in a high-risk clinical birth cohort. Second, to assess any influence from the fatty acid composition of mother's milk on the risk from breast-feeding. METHODS: We studied disease development during the first two years of life of the 411 infants from the Copenhagen Study on Asthma in Childhood (COPSAC) birth cohort, born to mothers with a history of asthma. We analyzed the effect from duration of breast-feeding before disease onset on the disease risk, avoiding the effect from disease-related modification of exposure (inverse causation). Polyunsaturated fatty acids were measured in breast milk. RESULTS: Breast-feeding significantly increased the risk of eczema adjusted for demographics, filaggrin variants, parents' eczema, and pets at home (N = 306; relative risk, 2.09; 95% CI 1.15-3.80; P = .016) but reduced the risk of wheezy episodes (relative risk, 0.67; 95% CI 0.48-0.96; P = .021) and of severe wheezy exacerbation (relative risk, 0.16; 95% CI 0.03-1.01; P = .051). There was no association between the fatty acid composition of mother's milk and the risk of eczema or wheeze. CONCLUSION: The risk of eczema was increased in infants with increasing duration of breast-feeding. In contrast, the risk of wheezy disorder and severe wheezy exacerbations was reduced. There were no significant effects from the fatty acid composition of the breast milk on risk of eczema or wheezy disorders.

Risk analysis of early childhood eczema.

BACKGROUND: The increasing prevalence of eczema suggests the role of environmental factors triggering a genetic predisposition. OBJECTIVE: To analyze the effect of environmental exposures in early life and genetic predisposition on the development of eczema before age 3 years. METHODS: The Copenhagen Study on Asthma in Childhood is a prospective clinical study of a birth cohort of 411 children born of mothers with asthma. Eczema was diagnosed, treated, and monitored at the clinical research unit, and complete follow-up for the first 3 years of life was available for 356 children. Risk assessments included filaggrin loss-of-function mutation; parent's atopic disease; sex; social status; previous deliveries; third trimester complications and exposures; anthropometrics at birth; month of birth; duration solely breast-fed; introduction of egg, cow's milk, and fish; time spent in day care; cat and dog at home; feather pillow; nicotine in infant's hair; and temperature and humidity in bedroom. RESULTS: Eczema developed in 43.5% of the infants. Filaggrin mutation (odds ratio [OR], 3.20; 95% CI, 1.46-7.02; P = .004), mother's eczema (OR, 2.80; 95% CI, 1.70-4.63; P < .0001), and father's allergic rhinitis (OR, 1.91; 95% CI, 1.09-3.33; P = .02) were directly associated with risk of eczema. Risk of eczema was significantly reduced by birth length (OR per cm increase, 0.87; 95% CI, 0.78-0.97; P = .02), increased bedroom temperature (probably inverse causality; OR, 0.80; 95% CI, 0.66-0.97; P = .02), and dog living in the home (OR, 0.44; 95% CI, 0.23-0.87; P = .02). CONCLUSIONS: Dog exposure reduced the risk of eczema, whereas short length at birth, filaggrin mutation, and parental atopy increased the risk of eczema by age 3 years.

Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure.

BACKGROUND: Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema. METHODS AND FINDINGS: We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27-4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79-32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24-1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13-3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35-10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16-2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation. CONCLUSIONS: We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.