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Background  Immune specific genes as well as genes regulating the formation of skin barrier are major determinants for eczema manifestation. There is a debate as to whether allergic sensitization and filaggrin gene ( FLG ) variants lead to eczema or  FLG  variants and eczema increase the risk of allergic sensitization. To investigate the time-order between eczema and allergic sensitization with respect to  FLG  variants, data from a large prospective study covering infancy to late adolescence were analyzed.    Methodology/Principal Findings  Repeated measurements of eczema and allergic sensitization (documented by skin prick tests) at ages 1, 2, 4, 10, and 18 years were ascertained in the Isle of Wight birth cohort (n = 1,456). Three transition periods were analyzed: age 1-or-2 to 4, 4 to 10, and 10 to 18 years.  FLG  variants were genotyped in 1,150 participants. Over the three transition periods, in temporal sequence analyses of initially eczema-free participants, the combined effect of  FLG  variants and allergic sensitization showed a 2.92-fold (95% CI: 1.47–5.77) increased risk ratio (RR) of eczema in subsequent examinations. This overall risk was more pronounced at a younger age (transition period 1-or-2 to 4, RR = 6.47, 95% CI: 1.96–21.33). In contrast,  FLG  variants in combination with eczema showed a weaker, but significant, risk ratio for subsequent allergic sensitization only up to 10 years of age.    Conclusions/Significance  Taking the time order into account, this prospective study demonstrates for the first time, that a combination of  FLG  variants and allergic sensitization increased the risk of eczema in subsequent years. Also  FLG  variants interacted with eczema and increased the risk of subsequent allergic sensitization, which, was limited to the younger age. Hence, early restoration of defective skin barrier could prevent allergic sensitization and subsequently reduce the risk of eczema development.

Interplay of Filaggrin Loss-of-Function Variants, Allergic Sensitization, and Eczema in a Longitudinal Study Covering Infancy to 18 Years of Age