Divisions of Rheumatology, Department of Internal Medicine II, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Arthritis Res Ther. 2012 Apr 18;14(2):R84. doi: 10.1186/ar3807.
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.
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.
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.
Thus, the TRAF3IP2-variant p.Asp10Asn is the only susceptibility allele with functional impact on TRAF6 binding, at least in the German population.
在最近针对银屑病关节炎（PsA）和寻常型银屑病的全基因组关联研究中，TRAF3IP2 基因中的常见编码变异被确定为这两种疾病的易感性的原因。p.Asp10Asn（rs33980500）的风险等位基因被证明与疾病的相关性最显著，并且编码的突变蛋白与 TRAF6 的结合特性几乎完全被破坏，支持其作为主要致病变异体和 IL-17 信号转导的调节剂的作用。
为了鉴定进一步的变体，在 871 名 PsA 患者中对编码两个已知 TNF 受体相关因子（TRAF）结合域的外显子 2-4 进行了测序。在 0.06%至 1.02%的等位基因中发现了 7 个错义变体和 1 个三碱基插入。这些变体中的 5 个也以相当的频率存在于 931 名对照个体中。构建了包含全长野生型或突变型 TRAF3IP2 的构建体，并用于在哺乳动物双杂交测定中分析所有变体与 TRAF6 结合的功能。
然而，新发现的等位基因没有一个编码与 TRAF6 或 IL-17 受体α链胞质尾结合具有不同特性的蛋白质，这表明它们不增加易感性。
因此，TRAF3IP2 变体 p.Asp10Asn 是唯一具有 TRAF6 结合功能影响的易感等位基因，至少在德国人群中是如此。
