Finemapping of susceptibility loci for atopic dermatitis on chromosome 1q21.3 and chromosome 11q13.5

特应性湿疹（AE）和银屑病是两种常见的炎症性皮肤病，其表现、进展和结局是多因素和复杂的。它们受到多种遗传和环境因素相互作用的影响，因此很难确定导致病因、严重程度和进展的遗传成分。有趣的是，尽管AE和银屑病在临床和病理上有很大的不同，但遗传连锁研究表明几个易感基因座存在重叠。一个这样的共享基因座位于覆盖表皮分化复合体（EDC）的染色体1q21.3上，其是在分化表皮的最上层中发现的编码分子的基因簇。最近已鉴定出丝聚蛋白（FLG）是AE的强EDC易感基因。然而，FLG突变仅部分解释了AE与EDC的遗传连锁，并显示出约40%的降低的突变率。因此，在一项针对AE的大型全基因组关联研究（GWAS）中，我们获得了EDC中其他风险变异的证据。关于银屑病，到目前为止，尚未确定负责1q21.3连锁信号的易感性变体，但最近的GWAS证实EDC内存在银屑病位点。因此，可能有一些EDC基因表现出不同类型的突变，这些突变容易导致AE或银屑病。另外，可能有两个或两个以上的物理上接近和遗传相似的基因，编码功能相关，但不同的分子，这可能会引起银屑病或AE的多态性。根据以前的调查和目前的全基因组数据，目前的建议旨在进一步精细映射和分子特征的EDC内的基因和他们的作用AE和银屑病。

Atopic eczema (AE) and psoriasis are two common inflammatory skin diseases which are multifactorial and complex in their presentation, progression, and outcome. They are influenced by the interaction of multiple genetic and environmental factors, making it challenging to identify genetic components responsible for the cause, severity, and progression. Interestingly, although clinically and pathologically AE and psoriasis are quite different, genetic linkage studies indicate an overlap of several susceptibility loci. One such shared locus is located on chromosome 1q21.3 overlying the epidermal differentiation complex (EDC), which is cluster of genes encoding molecules found in the uppermost layers of the differentiating epidermis. With filaggrin (FLG) a strong EDC susceptibility gene for AE has recently been identified. However, FLG mutations account only partially for the genetic linkage of AE to the EDC, and show a reduced penetrance of approximately 40%. Accordingly, in a large genome-wide association study (GWAS) for AE we obtained evidence for additional risk variants within the EDC. Concerning psoriasis, so far the susceptibility variant responsible for the linkage signal to 1q21.3 has not been identified, but a recent GWAS confirms presence of a psoriasis locus within the EDC. Thus, there might be EDC genes exhibiting distinct classes of mutations which predispose to either AE or psoriasis. Alternatively there might be polymorphisms in two or more physically close and genetically similar genes, encoding functionally related but nevertheless distinct molecules, which might give rise to either psoriasis or AE.Based on previous investigations and current genome-wide data the current proposal aims at further fine-mapping and molecular characterization of genes within the EDC and their role for AE and psoriasis.