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Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.

Capon, F, Bijlmakers, M, Wolf, N, Quaranta, M, Huffmeier, U, Allen, M, Timms, K, Abkevich, V, Gutin, A, Smith, R, Warren, RB, Young, H, Worthington, J, Burden, A, Griffiths, C, Hayday, A, Nestle, F, Reis, A, Lanchbury, J, Barker, J, Trembath, R

Human Molecular Genetics. 2008;17(13):1938-45.

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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 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.

Bibliographic metadata

Type of resource:
Content type:
Publication type:
Publication form:
Published date:
Journal title:
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Place of publication:
England
Volume:
17
Issue:
13
Start page:
1938
End page:
45
Total:
-1892
Pagination:
1938-45
Digital Object Identifier:
10.1093/hmg/ddn091
Access state:
Active

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Record metadata

Manchester eScholar ID:
uk-ac-man-scw:1d17544
Created:
30th August, 2009, 14:27:13
Last modified:
11th March, 2014, 11:17:09

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