Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity

S Kezic, G M O'Regan, N Yau, A Sandilands, H Chen, L E Campbell, K Kroboth, R Watson, M Rowland, W H Irwin McLean, A D Irvine, S Kezic, G M O'Regan, N Yau, A Sandilands, H Chen, L E Campbell, K Kroboth, R Watson, M Rowland, W H Irwin McLean, A D Irvine

Abstract

Background: Filaggrin, coded by FLG, is the main source of several major components of natural moisturizing factor (NMF) in the stratum corneum (SC), including pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). Loss-offunction mutations in FLG lead to reduced levels of filaggrin degradation products in the SC. It has recently been suggested that expression of filaggrin may additionally be influenced by the atopic inflammatory response. In this study, we investigated the levels of several breakdown products of filaggrin in the SC in healthy controls (CTRL) and patients with atopic dermatitis (AD) in relation to FLG null allele status. We examined the relationship between NMF (defined here as the sum of PCA and UCA) and AD severity.

Methods: The SC levels of filaggrin degradation products including PCA, UCA, histidine (HIS) and tyrosine were determined in 24 CTRL and 96 patients with moderate-to-severe AD. All subjects were screened for 11 FLG mutations relevant for the study population.

Results: The levels of PCA, UCA and HIS correlated with FLG genotype. Furthermore, these levels were higher in the CTRL when compared to AD patients with no FLG mutations. Multiple regression analysis showed that NMF levels were independently associated with FLG genotype and severity of disease.

Conclusion: Decreased NMF is a global feature of moderate-to-severe AD; within AD, FLG genotype is the major determinant of NMF, with disease severity as a secondary modifier. NMF components are reliably determined by a noninvasive and relatively inexpensive tape stripping technique.

© 2011 John Wiley & Sons A/S.

Figures

Figure 1
Figure 1
Filaggrin degradation products (geometric mean and 95% CI) in healthy controls (CTRL) and patients with atopic dermatitis (AD) in relation to FLG genotype. For statistic analysis, all data were log-transformed. Within AD patient subgroups, anova analysis with a post hoc Tukey multiple correction has been applied. To test differences between CTRL and ADNON-FLG (FLG+/+), the one-tailed Student’s t-test was used. *P < 0.05, **P < 0.01; ***P < 0.001.
Figure 2
Figure 2
Levels of tyrosine (geometric mean and 95% CI) in relation to FLG genotype.
3
3
Correlation between the levels of tyrosine and pyrrolidone carboxylic acid + urocanic acid + histidine in (A) healthy controls and FLG+/+ and in (B) FLG+/− and FLG−/−. The outlier in (B) was excluded in the linear regression analysis. r, Pearson’s correlation coefficient.

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