炎症性肠病活动威胁强直性脊柱炎：孟德尔随机化与转录组分析的启示。

BACKGROUND: Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) share common traits of chronic recurrent inflammation affecting both the intestines and joints. Epidemiological studies have revealed that the incidence of AS has jumped from 0.3% to 3% among patients with IBD. However, these findings do not definitively establish a causal relationship whereby IBD directly leads to the development of AS. Moreover, whether the activity of IBD will have an impact on this process remains a pending question. METHODS: Two-sample Mendelian randomization (MR) analyses were employed across multiple datasets to investigate the potential of IBD as a risk factor for AS. The pathogenic genes of AS were identified by MR analysis of expression quantitative trait locus. Risk scores for active and inactive patients were calculated by single-sample gene set enrichment analysis. Comparative assessments encompassing alterations in risk transcription factor activity, shifts in signaling pathways, and variances in immune cell profiles were conducted between active and inactive patients. Moreover, the correlation of immune cells and risk genes was quantified. RESULTS: A total of 6 MR analyses, conducted across 3 exposure datasets and 2 outcome datasets, consistently revealed that IBD substantially elevates the risk of AS development. The MR analysis of the two outcome datasets identified 66 and 54 risk genes, respectively. Notably, both the risk scores computed from the two distinct sets of risk genes were notably higher in active patients compared to their inactive counterparts. Discernible variations in the activity of risk-associated transcription factors were observed between active and inactive patients. In addition, three inflammatory pathways exhibited marked activation in active patients. Moreover, seven specific immune cell types, closely linked to disease activity, exhibited statistically significant correlations with the identified risk genes. CONCLUSION: By combining Mendelian randomization with transcriptome analysis, this study postulates IBD as a significant risk factor for AS, and further presents innovative evidence for the impact of IBD activity on the progression of AS.

背景：炎症性肠病（IBD）和强直性脊柱炎（AS）具有共同的慢性复发性炎症特征，影响肠道和关节。流行病学研究表明，IBD 患者中 AS 的发病率从 0.3%跃升至 3%。然而，这些发现并不能明确确定 IBD 直接导致 AS 发展的因果关系。此外，IBD 的活动是否会对此过程产生影响仍是一个悬而未决的问题。

方法：采用两样本孟德尔随机化（MR）分析方法，通过多个数据集探讨 IBD 作为 AS 风险因素的可能性。通过 MR 分析表达数量性状基因座确定 AS 的致病基因。通过单样本基因集富集分析计算活动和不活动患者的风险评分。对活动和不活动患者之间的风险转录因子活性变化、信号通路变化和免疫细胞谱变化进行比较评估。此外，量化了免疫细胞和风险基因之间的相关性。

结果：共进行了 6 项 MR 分析，涉及 3 个暴露数据集和 2 个结局数据集，结果一致表明 IBD 显著增加了 AS 发展的风险。两个结局数据集的 MR 分析分别确定了 66 个和 54 个风险基因。值得注意的是，从两个不同的风险基因集计算出的风险评分在活动患者中均显著高于不活动患者。在活动和不活动患者之间观察到风险相关转录因子活性的明显变化。此外，三个炎症途径在活动患者中表现出明显的激活。此外，七种与疾病活动密切相关的特定免疫细胞类型与鉴定出的风险基因存在显著相关性。

结论：通过将孟德尔随机化与转录组分析相结合，本研究提出 IBD 是 AS 的一个重要危险因素，并进一步提供了 IBD 活动对 AS 进展影响的创新性证据。