Gene-environment interactions in childhood eczema: Elder siblings enhance the effect of filaggrin mutations – Results from the LISAplus and GINIplus study

Abstract

Background: Several studies showed a protective effect of elder siblings on eczema development, which is in line with the hygiene-hypothesis. However, findings are not consistent and there might exist different causal pathways for the development of eczema. Especially barrier disturbances as found in children with filaggrin (FLG) mutations seem to play an important role. We hypothesized, that the dysfunction in skin barrier in children with FLG loss-of-function mutations may modulate the sibling-effect. Therefore we investigated the interaction between FLG mutations and the presence of elder siblings on the development of eczema in 2 independent birth cohorts. Materials and Methods: We used data from 2 German birth cohorts (LISAplus, GINIplus) up to the age of 6 years. Genotyping for FLG mutations (R501X, 2282del4) was performed in 1039 (LISAplus) and 1828 (GINIplus) children. Data on eczema (diagnosis and symptoms) and elder siblings were obtained by parental questionnaires. The association between eczema, FLG-mutations and elder siblings was analysed longitudinally, using generalized estimating equations. Results: We found no protective effect of elder siblings on eczema development. On the contrary, the risk for eczema was significantly enhanced in children with FLG mutations if they had elder siblings. In LISAplus the ORs for the effect of elder siblings on eczema were 1.01 (CI: 0.74–1.37) for children without FLG mutations and 3.31 (CI: 1.21–9.04) for children with FLG mutations. In GINIplus the ORs were 1.00 (CI: 0.80–1.23) and 2.39 (CI: 1.09–5.28), respectively. The interaction between FLG mutations and elder siblings was significant in both cohorts. Conclusions: We observed that there was no protective effect of elder siblings on the development of eczema in children with FLG mutations. – In contrast elder siblings enhanced the effect of FLG mutations. Our findings give evidence for complex skin driven pathogenic mechanisms in eczema development taking gene-environment interactions into account.