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

Abstract

Background: Associations of variants of the filaggrin gene, i.e. FLG 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 FLG variants need eczema and/or allergic sensitization as a necessary component to execute adverse effects on coexisting and subsequent asthma and rhinitis. Methods: 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. Results:FLG 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, ‘FLG variants plus allergic sensitization' and ‘FLG 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 FLG variants increased the risk of later rhinitis. Conclusions: Allergic sensitization and eczema modulated the association between FLG variants and asthma but not rhinitis. Our results imply that the mechanisms and pathways through which FLG variants predispose to an increased risk of asthma and rhinitis may be different.

Patterns of allergic sensitization and atopic dermatitis from 1 to 3 years: Effects on allergic diseases

“…Children with persistent poly‐sensitization to foods from 1 to 3 years of age concomitant with AD were at the highest risk for all the studied allergic diseases. Children with AD only were at risk for rhinitis and food allergy . On the other hand, although children who demonstrated mono‐sensitization to foods at 1 year tended to have transient sensitization that disappeared by 3 years, they were still at an increased risk for allergic outcomes, especially reported food allergy.…”

“…The heterogeneity of methods used in past cross‐sectional and cohort studies examining sensitization and AD as risk factors for allergic diseases makes interpretation difficult. Some examined only incident cases of AD, others assessed the risk of AD among all children and some did not distinguish between different types of sensitization . Ignoring the heterogeneity in the type of allergic sensitization (food, inhalant, food and inhalant, mono‐sensitization and poly‐sensitization), time of manifestation (persistent or transient) and AD status by simply categorizing children as “atopic” and “non‐atopic” may obscure differential impacts of these risk factors .…”

“…Some examined only incident cases of AD, 12,13 others assessed the risk of AD among all children and some did not distinguish between different types of sensitization. 1,[12][13][14][15][16][17][18] Ignoring the heterogeneity in the type of allergic sensitization (food, inhalant, food and inhalant, mono-sensitization and poly-sensitization), time of manifestation (persistent or transient) and AD status by simply categorizing children as "atopic" and "non-atopic" may obscure differential impacts of these risk factors. [6][7][8][9][10] For instance, an increased risk for hospitalizations due to asthma was only found among children who were poly-sensitized at an early age but not among those sensitized at a later age.…”

Altered Expression of Genes Encoding Cornulin and Repetin in Atopic Dermatitis

“…There are ethnic differences in the frequency of FLG mutations, and local differences exist even within Europeans regions [13,14] . It is worth mentioning that the FLG deficiency in AD is caused not only by gene mutations but also by other exogenous and immunological factors which influence FLG expression [15,16] . It has been proven that water, low humidity, skin irritants, sunburn, micro-organisms colonizing the skin, and the Th2 cytokines (e.g.…”

Significance of the epidermal barrier and sensitisation to household allergens to the development of atopic march for primary prevention

“…Так, было показано, что у детей со среднетяжелым или тяжелым атопи-ческим дерматитом и мутацией гена филаггри-на статистически чаще отмечается тенденция к увеличению частоты встречаемости сенсибилиза-ции к аллергенам домашней пыли и ýпидермису кошки, и для данных пациентов харктерны высо-кие концентрации специфических IgE-антител к ýпидермису кошки [12]. Наличие мутаций в гене FLG повышает риск развития астмы (ОР 1,39), при ýтом одновременное наличие атопического дерматита усиливает данный риск (ОР 1,56) [13]. A. Dębińska и соавт.…”