title: Identification of low-frequency TRAF3IP2 coding variants in psoriatic arthritis patients and functional characterization.
abstract: BACKGROUND
  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.
authors.affiliation: Divisions of Rheumatology, Department of Internal Medicine II, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Böhm
authors.forename: Harald
authors.initials: H
authors.lastname: Burkhardt
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.forename: Maria
authors.initials: M
authors.lastname: Apel
authors.forename: Frank
authors.initials: F
authors.lastname: Behrens
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hüffmeier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D015535:Arthritis, Psoriatic / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D005815:Genetic Code / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D048029:TNF Receptor-Associated Factor 6; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins