Filaggrin gene mutations in the Dutch population

FLG mutations R501X, 2282del4, and R2447X were genotyped in the PIAMA birth cohort (n=934) to evaluate longitudinally their association with eczema, specific IgE sensitization, asthma combined with bronchial hyperresponsiveness and hay fever up to 8 years of age and their interaction with cat exposure. Combined FLG mutations were significantly associated with eczema at all ages that started in the first year. The association between the major 2282del4 variant and eczema up to age 8 was stronger in children with a cat at home (OR=6,0; 95% CI, 3,2-11,3). A significant association between 2282del4 and sensitization (specific IgE =0.70 kU/L) was only found in children with early-life cat exposure (OR=5,4; 95% CI, 1,2-23,6). The distribution of FLG variants was not significantly different between atopic and nonatopic eczema and both were significantly associated with the combined genotype. The prevalence of asthma at 0 to 8 years combined with bronchial hyperresponsiveness at 8 years was significantly associated with the combined genotype (OR=3,7; 95% CI, 1,8-7,5). Hay fever was significantly associated with 2282del4 from age 5 onwards (OR=3,9; 95% CI, 1,5-10,5). In conclusion, analyses of the longitudinal data showed that eczema in the first year is a primer determinant of an association between FLG variants and later development of asthma, and hay fever. The 2282del4 variant was significantly associated with sensitization only in children with early-life cat exposure. There likely are two subgroups of children with early onset eczema and FLG mutations: one group that walks an atopic march that starts in the skin, and one group that does not walk the march to allergy.