Association Screening in the Epidermal Differentiation Complex (EDC) Identifies an SPRR3 Repeat Number Variant as a Risk Factor for Eczema
Association Screening in the Epidermal Differentiation Complex (EDC) Identifies an SPRR3 Repeat Number Variant as a Risk Factor for Eczema
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DOI：
10.1038/jid.2011.90
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发表时间：
2011-08-01
影响因子：
6.5
通讯作者：
Lee, Young-Ae
中科院分区：
文献类型：
--
作者：
Marenholz, Ingo;Rivera, Vladimir A. Gimenez;Lee, Young-Ae
遗传决定的皮肤屏障损伤是湿疹的主要原因。由于表皮分化复合体（EDC）中存在许多对完整表皮至关重要的基因，因此我们筛选了国家生物技术信息中心（NCBI）数据库中EDC基因中的pupirine功能多态性，并测试了它们与湿疹的相关性。我们确定了20个预测对蛋白质功能有重大影响的多态性。其中4个在94例湿疹患者中得到验证：FLG 2无义突变（rs 12568784）、LCE 1D终止密码子突变（rs 41268500）、SPRR 3 24 bp缺失（rs 28989168）和S100 A3移码突变（rs 11390146）。次要等位基因频率分别为15.1、6.1、47.2和0.4%。在555名湿疹患者和375名对照中验证的多态性的关联测试确定了rs 28989168（SPRR 3）对湿疹的显著影响。这种关联在另外1,314例病例和1,322例对照中得到了重复，显性遗传模式的总体优势比为1.30（95%置信区间1.12-1.51; P = 0.00067）。富含脯氨酸的小蛋白（SPRRs）是上皮细胞膜上的一种跨膜蛋白，为复层鳞状上皮细胞提供了主要的屏障功能。与湿疹相关的SPRR 3变体在中央结构域携带额外的24 bp重复序列，这可能会改变CE的物理性质。
The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function. Of these, 4 were validated in 94 eczema patients: a nonsense mutation in FLG2 (rs12568784), a stop codon mutation in LCE1D (rs41268500), a 24-bp deletion in SPRR3 (rs28989168), and a frameshift mutation in S100A3 (rs11390146). The minor allele frequencies were 15.1, 6.1, 47.2, and 0.4%, respectively. Association testing of the validated polymorphisms in 555 eczema patients and 375 controls identified a significant effect of rs28989168 (SPRR3) on eczema. The association was replicated in another 1,314 cases and 1,322 controls, yielding an overall odds ratio of 1.30 (95% confidence interval 1.12-1.51; P = 0.00067) for a dominant mode of inheritance. Small proline-rich proteins (SPRRs) are crossbridging proteins in the cornified cell envelope (CE), which provides the main barrier function of stratified squamous epithelia. The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the CE.