The effects from FLG mutations in both cohorts occurred early in life as demonstrated by the Kaplan Meier curves ( and ), with hazard ratios (HR) of 2.90 (1.80–4.68) and 2.06 (1.40–3.05) in the first year and 0.71 (0.22–2.27) and 1.01 (0.48–2.51) after age 1 y (COPSAC and MAAS, respectively). We therefore focused the analysis on the interaction between FLG status and environmental exposures during the first year of life. Exposure variables in both cohorts were independent of FLG mutations.
Kaplan-Meier Estimates of Cumulative Risk of Eczema in the COPSAC Cohort with and without FLG Mutation
Kaplan-Meier Estimates of Cumulative Risk of Eczema in the MAAS Cohort with and without FLG Mutation
Of 411 infants, 379 of mixed European ancestry were genotyped for 501x and 2282del4 [1
] as well as R2448X and S3247X [15
]. The main mutated alleles 501x and 2282del4 were present in 40 children and exhibited a very strong association to the development of eczema as previously reported [1
Eczema was diagnosed in 28% (105 children) before age 1 y; 265 (75%) did not have pets in their home at birth, 38 (11%) had a cat, 37 (11%) had a dog, and 11 (3%) had both; information on pet ownership was not available in 28 children. Among the 38 children with main mutations and information on pet ownership, 26 (68%) did not have pets, seven (18%) had a dog only, four (11%) had a cat only, and one (3%) had both. Objective measure of allergen exposure was available in 339 children; 205 (60%) had low cat and dog allergen levels, 54 (16%) high cat allergen level, 54 (16%) high dog allergen level, 26 (8%) high cat and dog allergen levels, and 78 (23%) high mite allergen level. Among the 38 children with mutation, 22 (58%) had low cat and dog allergen levels, five (13%) high cat allergen level, nine (24%) high dog allergen level, two (5%) had high cat and dog allergen levels, and ten (26%) high mite allergen level. Six children were lost to follow-up during the first year but were included in the analyses for the available follow-up period.
Kaplan-Meier plots suggested an increased risk of eczema due to FLG mutation, and a further increased risk of eczema due to cat exposure but only in the presence of FLG mutation (). Backwards elimination in a multiple Cox regression including FLG status, cat exposure, dog exposure, mite allergen exposure, and interactions between FLG status and cat exposure, dog exposure, and mite allergen exposure showed a significant interaction between cat exposure and FLG status (p = 0.0008) and a significant effect of dog exposure (p = 0.05). An additional exploration of the cat exposure-FLG status interaction demonstrated an increased risk of developing eczema due to mutation (HR 2.26 [95% CI 1.27–4.00], p = 0.005), with an additional increased risk if also exposed to cat (HR 11.11 [3.79–32.60], p < 0.0001). The overall decrease in risk due to exposure to dog was quantified in an HR of 0.49 [0.24–1.01]. Analysis including only children carrying mutant alleles demonstrated a significant effect of cat ownership on development of eczema (HR 7.49 [2.37–23.67], p = 0.0006).
COPSAC: Kaplan-Meier Estimates of Cumulative Risk of Eczema during the First Year of Life Stratified on Mutation and Cat at Birth Status
For allergen exposure a similar analysis was made with cat, dog, and mite allergen levels. The model confirmed an increased risk of developing eczema due to mutation (HR 2.53 [1.45–4.41], p = 0.001) with an additional increase in risk if exposed to high cat allergen level (HR 3.77 [1.45–9.81], p = 0.006). In this analysis there was no significant effect of dog or mite allergens. Analysis including only children carrying mutant alleles demonstrated a significant effect of cat allergen exposure on development of eczema (HR 3.09 [1.17–8.19], p = 0.023).
Cat allergen exposure shows high agreement with reported cat exposure at 4 wk (simple Kappa coefficient 0.62 [0.51–0.73]). Similarly dog allergen exposure shows high agreement with reported dog exposure at 4 wk (simple Kappa coefficient 0.59 [0.48–0.70]).
S. aureus was identified from the perineum in one newborn before the age of 3 mo.
Of 940 children with questionnaire data on the age of onset of eczema, 513 provided a blood sample for DNA extraction. Children who provided DNA did not differ from those who did not in terms of family history, maternal age, socioeconomic status, history of eczema, allergic sensitisation, and pet ownership (data available on request).
A total of 503 children of mixed European ancestry had information on FLG main mutations (501x and 2282del4), pet ownership at birth, and the age of onset of eczema. By age 1 y, eczema was reported by 187/503 parents (37%). Mutated alleles were present in 50 children (10%); 324 (64%) did not own any pets at birth, 88 (18%) had a cat at home, 66 (13%) had a dog, and 25 (5%) had both. The frequency of pet ownership did not differ between children with or without FLG mutation (no pets 293/453 [64.7%] and 31/50 [62%], cat 77/453 [17%] and 11/50 [22%], dog 60/453 [13.2%] and 6/50 [12%], and both cat and dog 23/453 [5.1%] and 2/50 [4%], no FLG mutation versus FLG mutation, respectively, p = 0.84). Cat allergen exposure was available in 461 children, mite allergen in 458, and dog allergen in 460.
Kaplan-Meier plots demonstrating the age of onset of eczema in the first year of life related to cat and dog ownership amongst children with and without FLG mutation are presented in . The results of a multiple Cox regression that included FLG genotype, cat and dog ownership at birth, the interaction between FLG genotype with cat and dog ownership, and mite exposure and its interaction with FLG genotype indicated an increased risk of developing eczema in the first 12 mo due to FLG mutation (HR 1.95 [95% CI 1.13–3.36], p = 0.017). Furthermore, in the presence of FLG mutation, the risk increased further because of cat ownership at birth, with no significant effect of cat ownership being observed amongst children without FLG mutation (interaction of cat ownership at birth and FLG mutation, HR 3.82 [1.35–10.81], p = 0.011). There was a trend for dog ownership to increase the risk (HR 1.51 [0.96–2.37], p = 0.075), with no significant interaction of FLG genotype with dog ownership (HR 0.59 [0.16-2.20], p = 0.43) or mite allergen exposure (HR 1.15 [0.93–1.43], p = 0.21). There was no significant effect of having both cats and dogs (HR 1.57 [0.82–3.03]), or their interaction with FLG genotype (p = 0.96). Analysis including only children carrying mutant alleles demonstrated a significant effect of cat ownership on development of eczema (HR 2.47 [1.09–5.62], p = 0.03).
MAAS: Kaplan-Meier Estimates of Cumulative Risk of Eczema during the First Year of Life Stratified on Mutation and Cat at Birth Status
In terms of allergen exposure there was no significant correlation between mite, cat, and dog allergen levels. Multiple Cox regression that included FLG genotype, cat, dog, and mite allergen levels, and the interaction between genotype and allergen levels confirmed an increased risk of developing eczema due to mutation (HR 2.22 [1.27–3.89], p = 0.005) and the interaction between cat allergen and FLG genotype (with risk increasing risk with increasing allergen level among children with FLG mutation; HR for interaction 1.31 [1.03–1.67], p = 0.026). Nonsignificant trends were observed for dog allergen exposure (HR 1.07 [1.00–1.15], p = 0.06), the direction of which appeared to inverse in the interaction with FLG mutation (0.84 [0.68–1.05, p = 0.1]).
Allergic sensitisation was uncommon in early life in both cohorts (in COPSAC, cat sensitisation was detected in one infant with FLG mutation at 6 mo but none at 18 mo; in MAAS, two children were skin test positive to mite, four to cat, and three to dog at age 1 y). We therefore did not analyse sensitisation further.