Human Molecular Genetics Advance Access published online on March 25, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn091
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Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene
1 King's College London, Division of Genetics and Molecular Medicine, London, UK 2 King's College London, Division of Immunology, Infection and Inflammatory disease, London, UK 3 University of Erlangen-Nurnberg, Institute of Human Genetics, Erlangen, Germany 4 Myriad Genetics, Salt Lake City (UT), USA 5 University of Manchester, arc Epidemiology Unit, Manchester, UK 6 Department of Dermatology, Manchester, UK 7 University of Glasgow, Department of Dermatology, Glasgow, UK
* Corresponding author: Prof Richard C Trembath, Division of Genetics and Molecular Medicine, King's College School of Medicine, 9th Floor Tower Wing, Guy's Hospital, Great Maze Pond, SE1 9RT London, UK, Phone: +44-207-1887994; Fax: +44-207-1888050; E-mail: richard.trembath{at}genetics.kcl.ac.uk
Received December 21, 2007; Revised February 21, 2008; Accepted March 18, 2008
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 datasets confirmed this association, with SNP rs495337 yielding a combined P value of 1.4 x 10 –8, in an overall sample of 2,679 cases and 2,215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with 5 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. These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.
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