Lan Xiucai, Lan Xiuhua, Chang Ying, Zhang Xiaomin, Liu Jing, Vikash Vikash, Wang Wei, Huang Meifang, Wang Xiaobing, Zhou Feng, Chen Liping, Zhao Qiu
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.
The Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China.
Cell Physiol Biochem. 2017;41(5):2077-2090. doi: 10.1159/000475439. Epub 2017 Apr 14.
BACKGROUND/AIMS: To investigate the associations between the rs1250569 (zinc finger MIZ-type containing 1, ZMIZ1), rs1042522 (tumour protein p53, TP53), and rs10114470 (tumour necrosis factor-like cytokine 1A, TL1A) polymorphisms and the development of inflammatory bowel disease (IBD) in a Chinese (Han) population. We analysed the expression of genes that predispose patients to Crohn's disease (CD) and ulcerative colitis (UC).
A total of 381 IBD patients and 517 healthy controls were recruited into our study. Polymorphisms at the three loci were genotyped using polymerase chain reaction-ligation detection reactions (PCR-LDR). Genotype-phenotype correlations were analysed. Blood and gut samples were obtained and analysed using quantitative real-time PCR (qRT-PCR), western blot analysis, and immunohistochemistry to investigate the mRNA and protein levels and in situ expression of genes found to predispose patients to IBD. Furthermore, the expression of susceptible genes was further verified using a mouse dextran sulphate sodium (DSS)-induced acute colitis model.
No significant association was detected between rs1250569 and rs1042522 genotypes and CD or UC susceptibility. However, the frequency of allele A of rs1250569 was much higher in CD patients than that in healthy controls (55.03% vs. 48.48%, respectively; p = 0.044). The mutation rates at rs10114470 were dramatically lower at both the genotype and allele level in patients than those in healthy controls (p = 0.002 at both the genotype and allele level). Additionally, increased ZMIZ1 and TL1A levels were detected in intestinal samples obtained from both IBD patients and DSS-treated mice.
rs1250569 (ZMIZ1) and rs10114470 (TL1A) are two novel loci that indicate susceptibility to IBD in Han-Chinese patients. Consistent with previous studies, TL1A expression levels were higher in Chinese Han IBD patients and DSS-treated mice. Most importantly, we found that ZMIZ1 expression was markedly higher in both IBD patients and mice with experimentally induced colitis, suggesting that ZMIZ1 plays important roles in the pathogenesis of IBD.
背景/目的：研究rs1250569（含锌指MIZ型蛋白1，ZMIZ1）、rs1042522（肿瘤蛋白p53，TP53）和rs10114470（肿瘤坏死因子样细胞因子1A，TL1A）基因多态性与中国汉族人群炎症性肠病（IBD）发生发展之间的关联。我们分析了使患者易患克罗恩病（CD）和溃疡性结肠炎（UC）的基因表达情况。
本研究共纳入381例IBD患者和517例健康对照。采用聚合酶链反应-连接检测反应（PCR-LDR）对三个位点的多态性进行基因分型。分析基因型与表型的相关性。采集血液和肠道样本，采用定量实时聚合酶链反应（qRT-PCR）、蛋白质印迹分析和免疫组织化学方法，研究发现的使患者易患IBD的基因的mRNA和蛋白质水平以及原位表达情况。此外，使用小鼠葡聚糖硫酸钠（DSS）诱导的急性结肠炎模型进一步验证易感基因的表达。
未检测到rs1250569和rs1042522基因型与CD或UC易感性之间存在显著关联。然而，rs1250569的等位基因A在CD患者中的频率远高于健康对照（分别为55.03%和48.48%；p = 0.044）。rs10114470在患者中的基因型和等位基因水平的突变率均显著低于健康对照（基因型和等位基因水平均为p = 0.002）。此外，在IBD患者和DSS处理的小鼠的肠道样本中均检测到ZMIZ1和TL1A水平升高。
rs1250569（ZMIZ1）和rs10114470（TL1A）是两个新的位点，提示中国汉族IBD患者易感性。与既往研究一致，中国汉族IBD患者和DSS处理的小鼠中TL1A表达水平较高。最重要的是，我们发现IBD患者和实验性诱导结肠炎的小鼠中ZMIZ1表达均显著升高，提示ZMIZ1在IBD发病机制中起重要作用。
