Department of Medicine, Division of Gastroenterology, Infectiology and Rheumatology, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, Berlin 10117, Germany.
Int J Colorectal Dis. 2012 May;27(5):565-73. doi: 10.1007/s00384-011-1345-y. Epub 2011 Nov 9.
The aetiology of intestinal barrier dysfunction in Crohn's disease (CD) is poorly understood. Associations in relatives of CD families suggest a genetic basis, but the relevant variants are still unknown. We hypothesized that variants in genes occurring in pathways such as autophagy and IL23 signalling might contribute to CD by altering intestinal permeability.
We analysed five variants (rs10758669 within JAK2, rs744166 within STAT3, rs4958847, rs11747270 and rs13361189 within IRGM) in adult German inflammatory bowel disease patients (CD, n = 464; ulcerative colitis (UC), n = 292) and matched healthy controls (n = 508). These data were correlated with gastrointestinal permeability as assessed by lactulose/mannitol ratio in CD patients (n = 141) in remission.
Our data confirm the association between JAK2 rs10758669 (p = 0.026, OR = 1.25, 95% CI = 1.04-1.50) and STAT3 rs744166 (p = 0.04, OR = 0.83, 95% CI = 0.688-0.998) with CD, but not UC. With respect to all the analysed IRGM variants, no association was found to either CD or UC. Among CD patients, an increased intestinal permeability was detected in 65 out of 141 patients (46.1%). Most importantly, patients carrying the C risk allele within JAK2 rs10758669 displayed an increased permeability more often compared with patients without the C allele (p = 0.004). No association with intestinal permeability was found for STAT3 rs744166 and all IRGM variants.
JAK2 rs10758669 and STAT3 rs744166 increase susceptibility for CD. We show that the A>C substitution in rs10758669 of the JAK2 gene is associated with increased intestinal permeability. Altering intestinal barrier function might thus be one mechanism how JAK2 contributes to CD pathogenesis.
克罗恩病（CD）肠道屏障功能障碍的病因尚不清楚。CD 家族亲属的关联表明存在遗传基础，但相关变异仍不清楚。我们假设，在自噬和 IL23 信号等途径中发生的基因变异可能通过改变肠道通透性而导致 CD。
我们分析了德国炎症性肠病患者（CD，n=464；溃疡性结肠炎（UC），n=292）和匹配的健康对照者（n=508）中五个变异体（JAK2 内的 rs10758669、STAT3 内的 rs744166、rs4958847、rs11747270 和 IRGM 内的 rs13361189）。在缓解期的 CD 患者（n=141）中，我们通过乳果糖/甘露醇比值评估胃肠道通透性，并将这些数据与上述变异体相关联。
我们的数据证实了 JAK2 rs10758669（p=0.026，OR=1.25，95%CI=1.04-1.50）和 STAT3 rs744166（p=0.04，OR=0.83，95%CI=0.688-0.998）与 CD 相关，但与 UC 无关。对于所有分析的 IRGM 变异体，它们与 CD 或 UC 均无关。在 141 名 CD 患者中，有 65 名患者（46.1%）检测到肠道通透性增加。最重要的是，与不携带 C 风险等位基因的患者相比，携带 JAK2 rs10758669 的 C 风险等位基因的患者更常表现出通透性增加（p=0.004）。STAT3 rs744166 和所有 IRGM 变异体与肠道通透性均无关联。
JAK2 rs10758669 和 STAT3 rs744166 增加了 CD 的易感性。我们表明，JAK2 基因中 rs10758669 的 A>C 取代与肠道通透性增加有关。因此，改变肠道屏障功能可能是 JAK2 导致 CD 发病机制的一种机制。
