Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene
Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene
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DOI：
10.1093/hmg/ddn091
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发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Trembath, Richard C.
中科院分区：
文献类型：
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作者：
Capon, Francesca;Bijlmakers, Marie-Jose;Trembath, Richard C.
牛皮癣是一种免疫介导的皮肤疾病，是一种多因素遗传的特征。连锁研究已经清楚地确定了位于主要组织相容性复合体（MHC）内的原发疾病易感性位点，但对其他基因组区域产生了相互矛盾的结果。为了克服这一困难，我们进行了全基因组关联扫描，在318例病例和288例对照的初始样本中分析了超过408000个snp。在MHC之外，我们观察到一个单一的疾病相关标记簇，在染色体20q13上跨越47 kb。对两个复制数据集的分析证实了这种关联，在2679例病例和2215例对照的总样本中，SNP rs495337的综合p值为1.4 x 10（-8）。Rs495337映射到SPATA2转录本，与相邻的ZNF313基因（也称为RNF114）中的5个snp处于绝对连锁不平衡状态。Real-time PCR实验显示，与SPATA2不同，ZNF313在皮肤、t淋巴细胞和树突状细胞中大量表达。此外，对Genevar数据库中表达数据的分析表明，rs495337与ZNF313转录本水平升高相关（P = 0.003），表明该疾病易感等位基因可能是rs495337标记的ZNF313调控变异体。同源性研究表明，ZNF313是调节t细胞活化的泛素连接酶trac1的同源物。我们进行了无细胞实验，证实了ZNF313与trac1一样，通过泛素相互作用基序（UIM）结合泛素。这些发现共同确定了一种新的牛皮癣易感基因，在免疫反应的调节中具有假定的作用。
Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage studies have clearly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), but have generated conflicting results for other genomic regions. To overcome this difficulty, we have carried out a genome-wide association scan, where we analyzed more than 408 000 SNPs in an initial sample of 318 cases and 288 controls. Outside of the MHC, we observed a single cluster of disease-associated markers, spanning 47 kb on chromosome 20q13. The analysis of two replication data sets confirmed this association, with SNP rs495337 yielding a combined P-value of 1.4 x 10(-8) in an overall sample of 2679 cases and 2215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with five SNPs lying in the adjacent ZNF313 gene (also known as RNF114). Real-time PCR experiments showed that, unlike SPATA2, ZNF313 is abundantly expressed in skin, T-lymphocytes and dendritic cells. Furthermore, an analysis of the expression data available from the Genevar database indicated that rs495337 is associated with increased ZNF313 transcripts levels (P = 0.003), suggesting that the disease susceptibility allele may be a ZNF313 regulatory variant tagged by rs495337. Homology searches indicated that ZNF313 is a paralogue of TRAC-1 , an ubiquitin ligase regulating T-cell activation. We performed cell-free assays and confirmed that like TRAC-1, ZNF313 binds ubiquitin via an ubiquitin-interaction motif (UIM). These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.