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.

中文翻译：

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半胱天冬酶募集结构域家族成员 14 及其遗传变异体 rs11652075 在皮肤丝聚蛋白稳态中的新作用

背景

低表皮聚丝蛋白 (FLG) 是特应性皮炎 (AD) 和过敏性合并症的危险因素。FLG突变不能完全解释表皮FLG水平的变化，强调其他基因位点也可能调节FLG表达。

客观的

我们试图确定调节FLG表达的基因位点并阐明它们的功能和机制后果。

方法

进行了一项全基因组关联研究，在儿童特应性皮炎进展为哮喘的机制中，AD 儿童病变和基线非（从不）病变皮肤中的定量皮肤FLG表达。聚集规则间隔的短回文重复方法用于创建仅在已识别的变体 rs11652075 和半胱天冬酶募集结构域家族成员 14 ( CARD14 ) 缺陷的角质形成细胞中不同的同基因人类角质形成细胞，用于随后的机制研究。

结果

全基因组关联研究确定CARD14 rs11652075 变体与 AD 儿童非（从未）损伤皮肤中的FLG表达相关。Rs11652075 是人皮肤和原代人角质形成细胞中的CARD14表达数量性状基因座。与 CC 原代人角质形成细胞相比，T 变体破坏了功能性胞嘧啶-磷酸-鸟嘌呤位点，导致 TT 和 CT 中该位点（但不是相邻位点）的胞嘧啶-磷酸-鸟嘌呤甲基化减少以及特应性皮炎进展为哮喘的机制在儿童皮肤样本中，rs11652075 增加CARD14以等位基因特异性方式表达。此外，对聚集的规则间隔的短回文重复产生的 CC 和 TT 同基因角质形成细胞以及 CARD14-haplosufficient 和缺陷角质形成细胞的研究表明，IL-17A 通过 CARD14 调节FLG表达，其潜在机制取决于 rs11652075 基因型.

结论

我们的研究将CARD14确定为AD 儿童皮肤中FLG表达的新调节剂。此外，CARD14以依赖 rs11652075 的方式调节皮肤FLG稳态。