Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.
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.
Capon
Francesca
F
Division of Genetics and Molecular Medicine, Infection and Inflammatory Disease, King's College London, London, UK.
Bijlmakers
Marie-José
MJ
Wolf
Natalie
N
Quaranta
Maria
M
Huffmeier
Ulrike
U
Allen
Michael
M
Timms
Kirsten
K
Abkevich
Victor
V
Gutin
Alexander
A
Smith
Rhodri
R
Warren
Richard B
RB
Young
Helen S
HS
Worthington
Jane
J
Burden
A David
AD
Griffiths
Christopher E M
CE
Hayday
Adrian
A
Nestle
Frank O
FO
Reis
Andre
A
Lanchbury
Jerry
J
Barker
Jonathan N
JN
Trembath
Richard C
RC
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D011565:Psoriasis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D006113:United Kingdom
D002352:Carrier Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C425523:SPATA2 protein, human; D025801:Ubiquitin; C477146:RNF114 protein, human; D044767:Ubiquitin-Protein Ligases