Supplementary Material for: Association of Filaggrin Variants with Asthma and Rhinitis: Is Eczema or Allergic Sensitization Status an Effect Modifier?

<b><i>Background:</i></b> Associations of variants of the filaggrin gene, i.e. <i>FLG</i> with asthma and rhinitis have been shown to be modulated by eczema status. However, it is unknown whether allergic sensitization status modifies this association. The aim of this study was to determine whether <i>FLG</i> variants need eczema and/or allergic sensitization as a necessary component to execute adverse effects on coexisting and subsequent asthma and rhinitis. <b><i>Methods:</i></b> In the Isle of Wight birth cohort, repeated measurements of asthma, rhinitis, eczema and allergic sensitization (documented by skin-prick tests) were taken in 1,456 children at the ages of 1, 2, 4, 10 and 18 years. Filaggrin haploinsufficiency was defined as having at least the minor allele of R501X, 2282del4 or S3247X variants. log-binomial regression models were used to test associations and statistical interactions. <b><i>Results:</i></b><i>FLG</i> variants increased the risk of asthma [risk ratio (RR) 1.39, 95% confidence interval (CI) 1.06-1.80] and rhinitis (RR 1.37, 95% CI 1.16-1.63). In the delayed-effects models, ‘<i>FLG</i> variants plus allergic sensitization' and ‘<i>FLG</i> variants plus eczema' increased the risk of subsequent asthma by 4.93-fold (95% CI 3.61-6.71) and 3.33-fold (95% CI 2.45-4.51), respectively, during the first 18 years of life. In contrast, neither eczema nor allergic sensitization in combination with <i>FLG</i> variants increased the risk of later rhinitis. <b><i>Conclusions:</i></b> Allergic sensitization and eczema modulated the association between <i>FLG</i> variants and asthma but not rhinitis. Our results imply that the mechanisms and pathways through which <i>FLG</i> variants predispose to an increased risk of asthma and rhinitis may be different.