Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Abstract

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

Figure 1

Genome wide association results from the initial GWAS analysis. Negative decadic logarithms of genomic control corrected EIGENSTRAT p-values are plotted against genomic position (hg18). (a) Plot of 1,585,307 SNPs (after imputation) in 572 German psoriatic arthritis patients versus 888 German controls. The red line represents the genome wide significance threshold of 5×10⁻⁸. (b) Regional association of the TRAF3IP2 region. Genotyped SNPs appear in red, imputed SNPs in blue. Recombination rate (from HapMap data) is indicated by the light blue graph.

Figure 2

Haplotype and functional analysis of associated variants in TRAF3IP2. (a) Exon/intron structure of TRAF3IP2 with location of associated SNPs. The four most common haplotypes in a combined set of 2,077 PsA cases and 2,648 control individuals of European origin and their frequency within cases are given. Risk alleles are in bold type. For each haplotype, odds ratios and 95% confidence intervals (in brackets) compare occurrence of this vs. all three other haplotypes. (b) Interaction of wild type TRAF3IP2 (Act1) and PsA-associated variants D10N and R74W with TRAF6 in a mammalian two hybrid dual-luciferase reporter assay. Depicted are means of relative normalized luminescence units reflecting the specific induction of firefly-luciferase by the interaction of the cotransfected ligand pairs TRAF3IP2 and TRAF6 [blue bars]. The investigated TRAF3IP2-variants include constructs harboring either single missense variant (D10N or R74W) or both (D10N+R74W). To exclude autoactivation activity, each prey and bait construct was separately cotransfected with reporter plasmids into HEK293 cells in the absence of any potential interaction partner [open bars]. P53 andTRAF2 as a pair of non-interacting proteins served as an additional independent negative control. Error bars represent 95%-confidence intervals.