Novel role for caspase recruitment domain family member 14 and its genetic variant rs11652075 in skin filaggrin homeostasis - 03/02/22
Abstract |
Background |
Low epidermal filaggrin (FLG) is a risk factor for atopic dermatitis (AD) and allergic comorbidity. FLG mutations do not fully explain the variation in epidermal FLG levels, highlighting that other genetic loci may also regulate FLG expression.
Objective |
We sought to identify genetic loci that regulate FLG expression and elucidate their functional and mechanistic consequences.
Methods |
A genome-wide association study of quantified skin FLG expression in lesional and baseline non(never)-lesional skin of children with AD in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort was conducted. Clustered regularly interspaced short palindromic repeat approaches were used to create isogenic human keratinocytes differing only at the identified variant rs11652075, and caspase recruitment domain family member 14 (CARD14)-deficient keratinocytes for subsequent mechanistic studies.
Results |
The genome-wide association study identified the CARD14 rs11652075 variant to be associated with FLG expression in non(never)-lesional skin of children with AD. Rs11652075 is a CARD14 expression quantitative trait locus in human skin and primary human keratinocytes. The T variant destroys a functional cytosine-phosphate-guanine site, resulting in reduced cytosine-phosphate-guanine methylation at this site (but not neighboring sites) in TT and CT compared with CC primary human keratinocytes and Mechanisms of Progression of Atopic Dermatitis to Asthma in Children children’s skin samples, and rs11652075 increases CARD14 expression in an allele-specific fashion. Furthermore, studies in clustered regularly interspaced short palindromic repeat-generated CC and TT isogenic keratinocytes, as well as CARD14-haplosufficient and deficient keratinocytes, reveal that IL-17A regulates FLG expression via CARD14, and that the underlying mechanisms are dependent on the rs11652075 genotype.
Conclusions |
Our study identifies CARD14 as a novel regulator of FLG expression in the skin of children with AD. Furthermore, CARD14 regulates skin FLG homeostasis in an rs11652075-dependent fashion.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, filaggrin, CARD14, GWAS, skin, gene, skin barrier
Abbreviations used : AD, BCL10, CARD14, Cas9, CBM, CCL20, CpG, CRISPR-Cas9, CXCL8, eQTL, FLG, GWAS, MALT1, MAPK, MPAACH, NF-kB, SNP
Plan
| This work was supported by the National Institutes of Health (grant no, U19AI70235 to G.K.K.H., J.M.B., and L.J.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 149 - N° 2
P. 708-717 - février 2022 Retour au numéro
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