Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis
Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis
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DOI：
10.1053/j.gastro.2009.12.049
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发表时间：
2010-04-01
期刊：
影响因子：
29.4
通讯作者：
Marshall, John K.
中科院分区：
文献类型：
--
作者：
Villani, Alexandra-Chloe;Lemire, Mathieu;Marshall, John K.
背景与目的：急性肠胃炎是肠易激综合征（IBS）最强的危险因素。2000年5月，安大略沃尔克顿市（Walkerton, Ontario）有1,0002300名居民因市政供水受到微生物污染而患上肠胃炎；一项纵向研究发现，其中36.2%的人患上了肠易激综合征。我们使用这个队列来研究感染后(PI)-IBS的遗传易感性。方法：我们筛选了79个与血清素能通路、肠上皮屏障功能和先天免疫有关的基因功能变体，并在感兴趣的区域进行了精细的定位。我们比较了爆发后2至3年发生胃肠炎并报告PI-IBS的Walkerton居民（n = 228例）与发生胃肠炎但未发生PI-IBS的居民（n = 581例，对照组）的数据。结果：四种变异与PI-IBS相关，尽管在校正了单核苷酸多态性的总数后，这种关联并不显著。其中2个位于编码模式识别受体的TLR9中（rs352139, P545P, P = 0.0059; rs5743836, -T1237C, P = 0.0250; r(2) < 0.14）；1在编码紧密连接蛋白的CDH1中（rs16260,-C160A, P = 0.0352）；1在编码细胞因子的il - 6中（rs1800795,-G174C; P = 0.0420）。对这3个区域进行更密集的定位，发现1个新的IL6关联（rs2069861; P = 0.0069）， 14个关联可能与4个原始变异的连锁不平衡有关。在控制先前确定的临床危险因素时，TLR9、IL6和CDH1变异都是PI-IBS的独立危险因素。结论：这是第一项评估PI-IBS潜在遗传决定因素的描述性研究。编码参与上皮细胞屏障功能和肠道细菌先天免疫反应的蛋白的基因与急性胃肠炎后肠易激综合征的发生有关。
BACKGROUND & AIMS: Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS. METHODS: We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls). RESULTS: Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r(2) < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260,-C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795,-G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. CONCLUSION: This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS following acute gastroenteritis.