Lappalainen Maarit, Paavola-Sakki Paulina, Halme Leena, Turunen Ulla, Heliö Tiina, Färkkilä Martti, Kontula Kimmo
Research Program in Molecular Medicine, Biomedicum Helsinki, Helsinki, Finland.
Scand J Gastroenterol. 2006 Apr;41(4):424-9. doi: 10.1080/00365520500265166.
The two forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are thought to arise because of an interplay of unfavorable genetic and exogenous factors. During a genome-wide linkage study of IBD, we observed a nominal linkage to chromosome 11p12-q13 that was further confirmed upon fine density mapping. This chromosomal region contains a functional IBD candidate gene coding for tumor necrosis factor receptor-associated factor 6 (TRAF6), a signal transducer regulating innate and adaptive immunity as well as bone homeostasis.
Using denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing, all exons and exon-intron boundaries of the TRAF6 gene in probands of 95 IBD families were initially screened; this material comprised 20 CD, 39 UC and 36 mixed families.
No nucleotide changes in the coding sequence of TRAF6 were detected, but a single-base insertion/deletion polymorphism in a polythymine stretch (containing 8 or 7 thymines, respectively) in intron 3 was identified. However, examination of an extended material of 290 unrelated CD patients, 416 UC patients and 320 healthy blood donors failed to show any association with this 7T/8T variation and IBD, nor was this polymorphism related to specific clinical features in IBD.
Our study tends to exclude a good positional and functional candidate gene, TRAF6, as an IBD predisposing gene and lends support to the idea that the function of TRAF6 is important enough not to permit structural alterations of this mediator.
炎症性肠病（IBD）有两种形式，即克罗恩病（CD）和溃疡性结肠炎（UC），一般认为是由不利的遗传因素和外部因素相互作用引起的。在一项IBD全基因组连锁研究中，我们观察到与11号染色体p12 - q13存在名义上的连锁关系，精细密度定位进一步证实了这一点。该染色体区域包含一个功能性IBD候选基因，其编码肿瘤坏死因子受体相关因子6（TRAF6），这是一种调节先天性和适应性免疫以及骨稳态的信号转导分子。
采用变性高效液相色谱（dHPLC）和DNA测序技术，最初对95个IBD家系的先证者中TRAF6基因的所有外显子和外显子 - 内含子边界进行了筛查；这些材料包括20个CD家系、39个UC家系和36个混合家系。
在TRAF6编码序列中未检测到核苷酸变化，但在内含子3的一个多聚胸腺嘧啶序列（分别含有8个或个7胸腺嘧啶）中鉴定出一个单碱基插入/缺失多态性。然而，对290名无亲缘关系的CD患者、416名UC患者和320名健康献血者的扩展样本进行检测，未能发现该7T/8T变异与IBD之间存在任何关联，该多态性也与IBD的特定临床特征无关。
我们的研究倾向于排除一个良好的定位和功能候选基因TRAF6作为IBD易感基因，并支持这样一种观点，即TRAF6的功能足够重要，以至于不允许该介质发生结构改变。
