Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization

Language
en
Document Type
Article
Issue Date
2012-10-09
Issue Year
2011
Authors
Böhm, Beate
Burkhardt, Harald
Uebe, Steffen
Apel, Maria
Behrens, Frank
Reis, André
Hüffmeier, Ulrike
Editor
Abstract

Introduction 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. 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. Methods To 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. Results None 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. Conclusions Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population.

Journal Title
Arthritis Research & Therapy 14.2 (2012): 08.10.2012 <http://arthritis-research.com/content/14/2/R84>
Citation
Arthritis Research & Therapy 14.2 (2012): 08.10.2012 <http://arthritis-research.com/content/14/2/R84>
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