Identification of ZNF313 / RNF114 as a novel psoriasis susceptibility gene

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.

Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes

“…2 Genome-wide linkage scans have unambiguously mapped a primary disease susceptibility locus (PSORS1) to the major histocompatibility complex (MHC), 3 where refinement studies and resequencing efforts point to HLA-C as the most likely PSORS1 candidate. 4,5 More recently, the advent of genome-wide association scans has allowed the identification of several non-MHC susceptibility genes, including IL12B, IL23R, RNF114, TNFAIP3, TNIP1, IL4/IL13 and LCE3B/3C [6][7][8][9][10][11] Of these, IL12B and IL23R harbour variants that also confer susceptibility to Crohn's disease (CD) 12 and ankylosing spondylitis. 13 Similarly, TNFAIP3 alleles have been associated with rheumatoid arthritis, 14 systemic lupus erythematosus 15 and type I diabetes.…”

Fine mapping of eight psoriasis susceptibility loci

“…However, we did find nominally significant association for the already established signals in these two regions, rs9988642 chr1.hg19.g.67726104T4C (IL23R) and rs495337 chr20.hg19.g.48522330C4T (RNF114). 4,6,9 SNP rs495337 was genotyped in our data and had a P-value of 9.20 Â 10 À5 , whereas the SNP rs9988642 was imputed (estimated imputation r 2 ¼ 0.96) and had a P-value of 1.46 Â 10 À5 . Notably, rs9988642 is in strong LD with the rs11209026 chr1.hg19.g.67705958G4A variant, 7 which specifies glutamine at residue 381 in the IL-23 receptor, is associated with reduced risk of psoriasis, and abrogates signaling through the receptor.…”

“…Other important contributors include IL12B, IL23R, IL23A, TNFAIP3, IL13, RNF114 and TNIP1. [4][5][6]9 Although GWAS provides an efficient strategy for identifying disease susceptibility loci, detailed assessments of the contribution of these loci to disease require systematic investigation of common and rare variants in each locus. Previous fine-mapping studies in psoriasis have focused on the MHC, helping localize the primary risk locus 10,11 and identify multiple psoriasis susceptibility alleles.…”

Personalisierte Medizin

“…Neueste Daten haben ein gutes Ansprechen gezeigt (Flaherty, Infante et al, 2012 Genetik der Psoriasis ergab, dass sie eine der sogenannten komplexen genetischen Erkrankungen ist, mit mehr als 40 involvierten Genen (Capon et al, 2008;Nair et al, 2009;Strange et al, 2010;Tsoi et al, 2012), in denen Mutationen das Risiko für Psoriasis modulieren können. Die wichtigsten Gene wurden in der Region der HLA-Klasse-I-Moleküle identifiziert (Trembath et al, 1997 Lokalisationen des Körpers auf und wird in einer Zahl von 0 bis 72 zusammengefasst.…”