Analysis of keratin polypeptides 8 and 19 variants in inflammatory bowel disease
Analysis of keratin polypeptides 8 and 19 variants in inflammatory bowel disease
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DOI：
10.1016/j.cgh.2007.02.017
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发表时间：
2007-07-01
影响因子：
12.6
通讯作者：
Duerr, Richard H.
中科院分区：
文献类型：
--
作者：
Tao, Guo-Zhong;Strnad, Pavel;Duerr, Richard H.
背景/目的：角蛋白-8（KRT 8）缺失小鼠发生自发性结肠炎和肝损伤易感性。人类研究表明，一些KRT 8变体易患终末期肝病和进展，并表明这些变体可能与UC或CD相关。我们询问主要的肠角蛋白KRT 8或KRT 19的突变是否与UC/CD相关。方法：采用聚合酶链反应扩增KRT 8/KRT 19基因的外显子区域，使用来自2个独立组的基因组DNA。I组包括91例无关CD患者、93例无关UC患者和70例无关/未受影响的志愿者。KRT 8变体也在第II组中用焦磷酸测序进行了测试，该组包括682个独立的核心家庭，其中双亲和至少1个CD/UC受影响的后代以及273个未受影响的对照。两个队列均富含家族性IBD。结果如下：在组I中，在CD/UC患者的启动子和外显子1+2中鉴定出KRT 19变体，在对照/CD/UC组中具有相似的突变频率。相比之下，184例CD+UC患者中有16例携带KRT 8杂合变异，涉及Gly 62-to-Cys和Arg 341-to-His以及一种新的Arg 341-to-Cys，在4例志愿者中观察到（Arg 341-to-His），与广泛UC相关（P = .005）。一个父母未受影响的家庭有3个患有严重疾病的儿科受影响的兄弟姐妹，其中2人是复合杂合子（Gly 62-to-Cys/Arg 341-to-His）。然而，没有显着偏离随机传递的3个等位基因在第二组IBD家庭。结论：KRT 8和KRT 19变异体不过度传播或与家族性IBD相关，尽管不能排除在散发性IBD中的潜在作用。在IBD患者中发现了一种新的但罕见的角蛋白-8 Arg 341-to-Cys。
Background/Aims: Keratin-8 (KRT8)-null mice develop spontaneous colitis and predisposition to liver injury. Human studies show that some KRT8 variants predispose to end-stage liver disease and progression and suggest that such variants might associate with UC or CD. We asked whether mutations in KRT8 or KRT19, the major intestinal keratins, are associated with UC/CD. Methods: Exonic regions of the KRT8/KRT19 genes were polymerase chain reaction-amplified using genomic DNA from 2 independent groups. Group I included 91 unrelated patients with CD, 93 unrelated patients with UC, and 70 unrelated/unaffected volunteers. KRT8 variants were also tested with pyrosequencing in Group II that included 682 independent nuclear families with both parents and at least 1 CD/UC-affected offspring and 273 unaffected controls. Both cohorts were enriched for familial IBD. Results: In Group I, KRT19 variants were identified in CD/UC patients within the promoter and exons 1+2, with similar mutation frequencies in the control/CD/UC groups. In contrast, 16 of 184 CD+UC patients harbored KRT8 heterozygous variants involving Gly62-to-Cys and Arg341-to-His and a novel Arg341-to-Cys, which were noted in 4 volunteers (Arg341-to-His) and correlated with extensive UC (P = .005). One family with unaffected parents had 3 pediatric-affected siblings with severe disease, 2 of whom are compound heterozygous (Gly62-to-Cys/Arg341-to-His). However, there was no significant departure from random transmission of the 3 alleles in Group II IBD families. Conclusions: KRT8 and KRT19 variants are not overtransmitted or associated with familial IBD, although a potential role in sporadic IBD cannot be excluded. A novel but rare keratin-8 Arg341-to-Cys is identified in IBD patients.