背景:查明导致克罗恩病(CD)和溃疡性结肠炎(UC)的代谢物以了解其发病机理并确定可能的治疗靶标至关重要。为了实现这一目标,我们对日本CD和UC患者进行了首次全代谢组孟德尔随机化(MR)研究.
方法:作为暴露数据集,从东北医学Megabank组织获得了具有血液循环代谢产物的遗传仪器,其中包括来自7843名日本人的全基因组关联研究数据的204种代谢物。作为结果数据集,我们招募了日本的CD患者(n=1803),日本UC患者(n=1992),和健康对照(n=2022)。主要分析采用了逆方差加权法,而研究结果的稳定性则通过敏感性分析进行评估.
结果:单核苷酸多态性(SNP)过滤后,MR可获得45种代谢物的169个SNP。遗传预测的循环反式-戊二酸和色氨酸升高与较低的CD风险相关(比值比[OR],0.68;P=5.95×10-3;OR,0.64;分别为P=1.90×10-2)。遗传预测的咖啡酸升高与较低的UC风险相关(OR,0.67;P=4.2×10-4),在多次测试校正后仍然显著。我们确定了UC和3-羟基丁酸之间的因果关系(OR,2.21;P=1.41×10-2),反式戊二酸(OR,0.72;P=1.77×10-2),和2-羟基戊酸(OR,1.31;P=4.23×10-2)。没有证据表明这些候选代谢物具有多效性或反向因果效应。
结论:在我们的全代谢组MR研究中,我们发现咖啡酸对UC有显著的保护作用。
这项使用日本队列的全代谢组研究发现,咖啡酸可显著降低溃疡性结肠炎的风险,而3-羟基丁酸和2-羟基戊酸增加它。反式谷氨酸和色氨酸可降低克罗恩病的风险。
BACKGROUND: It is crucial to pinpoint the metabolites that cause Crohn\'s disease (CD) and ulcerative colitis (UC) to comprehend their pathogenesis and identify possible targets for therapy. To achieve this goal, we performed the first metabolome-wide Mendelian randomization (MR) study of Japanese patients with CD and UC.
METHODS: As exposure datasets, genetic instruments with blood-circulating metabolites were obtained from the Tohoku Medical Megabank Organization, which includes 204 metabolites from the genome-wide association study data of 7843 Japanese individuals. As outcome datasets, we enrolled Japanese patients with CD (n = 1803), Japanese patients with UC (n = 1992), and healthy controls (n = 2022). The main analysis utilized the inverse variance-weighted method, while stability of the findings was evaluated through sensitivity analyses.
RESULTS: After single nucleotide polymorphism (SNP) filtering, 169 SNPs for 45 metabolites were available for MR. Genetically predicted elevated circulating trans-glutaconic acid and tryptophan were associated with a lower CD risk (odds ratio [OR], 0.68; P = 5.95 × 10-3; and OR, 0.64; P = 1.90 × 10-2, respectively). Genetically predicted elevated caffeic acid was associated with a lower UC risk (OR, 0.67; P = 4.2 × 10-4), which remained significant after multiple testing correction. We identified a causal link between UC and 3-hydroxybutyrate (OR, 2.21; P = 1.41 × 10-2), trans-glutaconic acid (OR, 0.72; P = 1.77 × 10-2), and 2-hydroxyvaleric acid (OR, 1.31; P = 4.23 × 10-2). There was no evidence of pleiotropy or reverse causal effects for these candidate metabolites.
CONCLUSIONS: In our metabolome-wide MR study, we discovered a notable protective effect of caffeic acid against UC.
This metabolome-wide study using Japanese cohorts found that caffeic acid significantly reduces the risk of ulcerative colitis, while 3-hydroxybutyrate and 2-hydroxyvaleric acid increase it. Trans-glutaconic acid and tryptophan reduce the risk of Crohn’s disease.