runt相关转录因子3与溃疡性结肠炎相关，并与溶质载体家族22成员4和5表现出上位性。

Runt-related transcription factor 3 is associated with ulcerative colitis and shows epistasis with solute carrier family 22, members 4 and 5.

作者信息

Weersma Rinse K, Zhou Lu, Nolte Ilja M, van der Steege Gerrit, van Dullemen Hendrik M, Oosterom Elvira, Bok Lisette, Peppelenbosch Maikel P, Faber Klaas N, Kleibeuker Jan H, Dijkstra Gerard

机构信息

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

出版信息

Inflamm Bowel Dis. 2008 Dec;14(12):1615-22. doi: 10.1002/ibd.20610.

DOI:10.1002/ibd.20610

PMID:18668679

Abstract

BACKGROUND

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are intestinal inflammatory disorders with a complex genetic background. Mice deficient for the runt-domain-transcription-factor3 (Runx3) develop spontaneous colitis. Human RUNX3 resides in an IBD-susceptibility locus. We studied the association of RUNX3 in a cohort of IBD patients and analyzed the interaction with SLC22A4/5. RUNX3 and OCTN1 mRNA expression was assessed in inflamed and noninflamed mucosa from patients and controls.

METHODS

543 IBD patients (309 CD / 234 UC) and 296 controls were included. Four single nucleotide polymorphisms (SNPs) and 4 microsatellite markers were studied for RUNX3. Five SNPs (including SNP-207G-->C and SNP1672C-->T) were analyzed for SLC22A4/5. RUNX3, and OCTN1 expression in mucosal tissue from 30 patients (14 UC / 16 CD) and 6 controls were determined by quantitative polymerase chain reaction.

RESULTS

A significant association between RUNX3-SNP rs2236851 and UC (OR 1.61; 95% confidence interval [CI] 1.11-2.32, P = 0.020) was found. Carriership is associated with pancolitis (odds ratio [OR] 1.86; 95% CI 1.08-3.21). SLC22A4/5-SNPs rs272893 and rs273900 are associated with CD (OR 2.16; 95% CI 1.21-3.59 and OR 2.40; 95% CI 1.43-4.05). We found epistasis for carriership of a risk-associated allele in RUNX3 and SLC22A4/5 for UC patients versus CD patients (OR 3.83; 95% CI 1.26-11.67). RUNX3 mRNA expression is increased (P = 0.01) in inflamed colonic mucosa of UC patients compared to noninflamed mucosa and controls.

CONCLUSIONS

We provide evidence for the genetic association of RUNX3 with UC and for CD with the IBD5 locus including SLC22A4/5. An epistatic effect of RUNX3 and SLC22A4 was associated with an increased risk for UC. Our data suggest a role for RUNX3 in UC susceptibility.

摘要

背景

炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），是具有复杂遗传背景的肠道炎症性疾病。缺乏 runt 结构域转录因子 3（Runx3）的小鼠会发生自发性结肠炎。人类 RUNX3 位于 IBD 易感基因座。我们研究了 IBD 患者队列中 RUNX3 的关联性，并分析了其与 SLC22A4/5 的相互作用。对患者和对照的炎症及非炎症黏膜中 RUNX3 和 OCTN1 mRNA 表达进行了评估。

方法

纳入 543 例 IBD 患者（309 例 CD / 234 例 UC）和 296 例对照。对 RUNX3 研究了 4 个单核苷酸多态性（SNP）和 4 个微卫星标记。对 SLC22A4/5 分析了 5 个 SNP（包括 SNP - 207G→C 和 SNP1672C→T）。通过定量聚合酶链反应测定 30 例患者（14 例 UC / 16 例 CD）和 6 例对照的黏膜组织中 RUNX3 和 OCTN1 的表达。

结果

发现 RUNX3 - SNP rs2236851 与 UC 之间存在显著关联（比值比[OR]1.61；95%置信区间[CI]1.11 - 2.32，P = 0.020）。携带该基因与全结肠炎相关（比值比[OR]1.86；95%CI 1.08 - 3.21）。SLC22A4/5 - SNPs rs272893 和 rs273900 与 CD 相关（OR 2.16；95%CI 1.21 - 3.59 和 OR 2.40；95%CI 1.43 - 4.05）。我们发现 UC 患者与 CD 患者相比，RUNX3 和 SLC22A4/5 中风险相关等位基因的携带存在上位效应（OR 3.83；95%CI 1.26 - 11.67）。与非炎症黏膜和对照相比，UC 患者炎症性结肠黏膜中 RUNX3 mRNA 表达增加（P = 0.01）。