Rhodri Ll Smith

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.

Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease

Background: Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage analyses have clearly mapped a primary disease susceptibility locus to the major histocompatibility complex (MHC) region on chromosome 6p21. More recently, whole-genome association studies have identified two non-MHC disease genes (IL12B and IL23R), both of which also confer susceptibility to Crohn disease (CD). Objective and methods: To ascertain the genetic overlap between these two inflammatory conditions further, we investigated 15 CD-associated loci in a psoriasis case–control dataset. Results: The analysis of 1256 patients and 2938 unrelated controls found significant associations for loci mapping to chromosomes 1q24 (rs12035082, p = 0.009), 6p22 (rs6908425, p = 0.00015) and 21q22 (rs2836754, p = 0.0003). Notably, the marker showing the strongest phenotypic effect (rs6908425) maps to CDKAL1, a gene also associated with type 2 diabetes. Conclusions: These results substantiate emerging evidence for a pleiotropic role for s genes that contribute to the pathogenesis of immune-mediated disorders.

Investigation of association of the IL12B and IL23R genes with psoriatic arthritis.

Objective Recent reports have confirmed association of single-nucleotide polymorphisms (SNPs) mapping to the interleukin-23 receptor (IL-23R) and IL-12β genes with psoriasis susceptibility. The aim of this study was to determine whether these variants are also associated with susceptibility to psoriatic arthritis (PsA). Methods Two IL23R SNPs (rs7530511 and rs11209026) and 2 IL12B SNPs (rs3212227 and rs6887695) were genotyped in DNA samples from 520 white patients with PsA and 2,260 control subjects, all of whom resided in the UK. For SNP rs3212227, data on a larger group of controls (n = 4,681) were publicly available; this information was used in the analysis. Genotype counts were compared between patients with PsA and population controls, using the trend test. Results A haplotype comprising carriage of the common variants of both IL23R SNPs was associated with PsA susceptibility (adjusted P = 0.013 [1,000 permutations]). Both IL12B SNPs were independently associated with PsA susceptibility, and this association was strongest under a dominant model, with homozygosity for the common allele being more frequent in patients with PsA than in control subjects: for rs3212227, the odds ratio (OR) for carriage of AA versus other genotypes was 1.43 (95% confidence interval [95% CI] 1.17–1.76); for rs6887695, the OR for carriage of GG versus other genotypes was 1.43 (95% CI 1.18–1.74). Conclusion Variation within IL23R and IL12B is associated with susceptibility to both psoriasis and PsA. The effect sizes observed in patients with PsA appear to be smaller than those previously reported in patients with psoriasis, suggesting that both loci are primarily associated with psoriasis susceptibility. However, this does support the idea that the genetic etiology of the psoriasis present in patients with PsA has susceptibility loci in common with those observed in patients with uncomplicated psoriasis.

Genetic Variation in Efflux Transporters Influences Outcome to Methotrexate Therapy in Patients with Psoriasis

Methotrexate, an inexpensive first-line systemic therapy for moderate-to-severe psoriasis, is limited in its use by unpredictable efficacy and toxicity. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in methotrexate transmembrane transporters and adenosine receptors are associated with efficacy and/or toxicity of the drug. DNA was collected from 374 patients with chronic plaque psoriasis who had been treated with methotrexate. Phenotypic data on efficacy and toxicity were available. Haplotype tagging SNPs (r(2)>0.8) across the relevant genes, with a minor allele frequency of >5%, were selected from the HAPMAP phase II data. SNPs within the efflux transporter genes ABCC1 (ATP-binding cassette, subfamily C, member 1) and ABCG2 (ATP-binding cassette, subfamily G, member 2) are associated with good response to methotrexate therapy in patients with psoriasis; the former gene was also associated with the onset of toxicity. With one SNP in ABCC1, rs246240, the carriage of two copies of allele 1 gives an odds ratio of 2.2 (95% confidence interval: 1.3-3.6; P=0.001) for developing toxicity to methotrexate. These data indicate that knowledge of SNPs in genes relevant to methotrexate efflux may be important in selecting patients suitable for this therapy.

Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms

Background  The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug.

Genetic susceptibility to psoriasis: an emerging picture.

Psoriasis is recognized as a complex disease for which multiple genetic and non-genetic factors influence susceptibility. The major susceptibility locus resides in the MHC class I region and, until relatively recently, evidence for non-MHC loci was inconsistent. Like many common diseases, knowledge of the genetic basis of this condition has been advanced dramatically in recent times with the advent of genome-wide association studies using single nucleotide polymorphisms. Here, we give an overview of current knowledge of genetic risk factors for psoriasis and consider emerging studies that may further add to our understanding of the genetic basis of the disease.

No association between polymorphisms in the interleukin-15 gene and early-onset psoriasis in a UK cohort suggests heterogeneity for this susceptibility locus identified in Chinese psoriasis patients

Abbreviations: Kbp, kilo base pair; LD, linkage disequilibrium; PSORS, Psoriasis susceptibility locus; SNP, single-nucleotide polymorphism