Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA.
Gut. 2011 Dec;60(12):1671-1677. doi: 10.1136/gut.2011.241877. Epub 2011 Jun 2.
Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS.
Single nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case-control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A).
The Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10(-5); OR 1.37) and more pronouncedly, IBS-C (p=8.7×10(-7); OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033).
TNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.
肠易激综合征（IBS）是最常见的胃肠道疾病，影响全球超过 10%的普通人群。尽管怀疑存在遗传因素，但迄今为止尚未明确确定易感基因。本研究检验了这样一个假设，即有助于上皮屏障完整性、控制黏膜免疫反应以及与肠道细菌相互作用的基因与 IBS 相关。
在来自瑞典和美国的两个独立病例对照队列的 1992 名个体中，测试了与 30 个已知易感性位点的克罗恩病关联的最高信号相对应的单核苷酸多态性（SNP）对 IBS 风险的影响。关联测试包括对多个比较进行保守的 Bonferroni 校正，并且还在以便秘（IBS-C）、腹泻（IBS-D）或交替便秘和腹泻（IBS-A）为特征的特定患者亚组中进行了测试。
TNFSF15 基因中的克罗恩病风险等位基因 rs4263839G 与 IBS（p=2.2×10(-5)；OR 1.37）以及更明显的 IBS-C（p=8.7×10(-7)；OR 1.79）的风险增加显著相关。在单独分析的两个队列中也观察到了类似的关联和风险效应。在健康个体的外周血和直肠黏膜活检中均检测到 rs4263839 基因型与 TNFSF15mRNA 表达之间的相关性（合并 p=0.0033）。
TNFSF15 是 IBS 和 IBS 便秘的易感基因。由于 TNFSF15 编码的蛋白 TL1A 有助于炎症反应的调节，结果支持免疫激活在 IBS 中的作用。
