Abstract
IntroductionIn recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. The risk allele of p.Asp10Asn (rs33980500) proved to be most significantly associated and to encode a mutant protein with an almost completely disrupted binding property to TRAF6, supporting its impact as a main disease-causing variant and modulator of IL-17 signaling.MethodsTo identify further variants, exons 2-4 encoding both known TNF-receptor-associated factor (TRAF) binding domains were sequenced in 871 PsA patients. Seven missense variants and one three-base-pair insertion were identified in 0.06% to 1.02% of alleles. Five of these variants were also present in 931 control individuals at comparable frequency. Constructs containing full-length wild-type or mutant TRAF3IP2 were generated and used to analyze functionally all variants for TRAF6-binding in a mammalian two-hybrid assay.ResultsNone of the newly found alleles, though, encoded proteins with different binding properties to TRAF6, or to the cytoplasmic tail of the IL-17-receptor α-chain, suggesting that they do not contribute to susceptibility.ConclusionsThus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population.
Highlights
In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities
Because our case-control study of ~900 individuals was of limited power to exclude association to very-lowfrequency variants, we investigated the impact of amino acid changes encoded by the new TRAF3IP2-variants on functional properties of the nuclear factor-κB activator 1 (ACT1) protein by mammalian two-hybrid technology
None of the amino acid mutations in the full-length constructs of the new TRAF3IP2 coding variants exhibited any influence on TRAF6 binding (Figure 2)
Summary
In recent genome-wide association studies for psoriatic arthritis (PsA) and psoriasis vulgaris, common coding variants in the TRAF3IP2 gene were identified to contribute to susceptibility to both disease entities. We were able to identify the common coding variant p.Asp10Aspn (rs33980500) as the disease-causing allele with evidence from association findings at single nucleotide polymorphism (SNP) and haplotype levels, as well as binding studies of ACT1 with its interaction partner TRAF6 [2] (Figure 1). To find out whether low-frequency coding variants in TRAF3IP2 contribute to PsA susceptibility, we sequenced exons encoding TRAF-binding domains (Figure 1) [9] and studied their association with PsA as well as the functional consequences of the respective amino acid changes on interaction with TRAF6 and the interleukin-17 receptor a (IL17-RA)
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