Identification of ZNF313 / RNF114 as a novel psoriasis susceptibility gene
Open Access
- 25 March 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 17 (13), 1938-1945
- https://doi.org/10.1093/hmg/ddn091
Abstract
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 × 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.This publication has 33 references indexed in Scilit:
- T-cell regulator RNF125/TRAC-1 belongs to a novel family of ubiquitin ligases with zinc fingers and a ubiquitin-binding domainBiochemical Journal, 2008
- Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variantsNature Genetics, 2007
- PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage AnalysesAmerican Journal of Human Genetics, 2007
- Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controlsNature, 2007
- FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunityNature Genetics, 2007
- A Large-Scale Genetic Association Study Confirms IL12B and Leads to the Identification of IL23R as Psoriasis-Risk GenesAmerican Journal of Human Genetics, 2007
- Ubiquitylation and cell signalingThe EMBO Journal, 2005
- Haploview: analysis and visualization of LD and haplotype mapsBioinformatics, 2004
- Measuring inconsistency in meta-analysesBMJ, 2003
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001