Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China.
Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Front Immunol. 2023 Dec 11;14:1310086. doi: 10.3389/fimmu.2023.1310086. eCollection 2023.
Prior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research.
We aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach.
We selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn's disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation.
Genetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, = 1.60×10 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn's disease (OR: 0.71, 95% CI: 0.52-0.98, = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, = 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines.
Our study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.
先前的流行病学研究已经证实了炎症细胞因子与炎症性肠病（IBD）之间存在相关性。然而，这种关系的性质尚不确定。与传统的观察性研究相比，孟德尔随机化（MR）研究具有避免混杂和反向因果关系的优势。
我们旨在通过 MR 方法评估遗传决定的循环细胞因子水平与 IBD 风险之间是否存在关联。
我们从一项包含 8293 人的全基因组关联研究（GWAS）中选择了与 28 种细胞因子的循环水平相关的全基因组显著水平的遗传变异。IBD（包括克罗恩病和溃疡性结肠炎）的汇总数据来自国际炎症性肠病遗传学联合会和英国生物银行。我们使用逆方差加权法进行主要分析，并进行敏感性分析以测试结果的稳定性。随后，我们在英国生物银行数据集复制了 IBD 的结果。还进行了反向 MR 分析，以评估反向因果关系的可能性。
遗传预测的白细胞介素 17（IL-17）和干扰素-γ诱导的单核细胞趋化蛋白（MIG）水平升高与 IBD 的风险增加相关[比值比（OR）：1.52，95%置信区间（CI）：1.10-2.08， =0.010 用于 IL-17 和 OR：1.58，95% CI：1.24-2.00， = 1.60×10 用于 MIG]。此外，我们观察到 β-NGF 和 MIP-1β 与克罗恩病（OR：0.71，95% CI：0.52-0.98， = 0.039）和溃疡性结肠炎（OR：1.08，95% CI：1.01-1.15， = 0.019）的风险之间存在关联。在反向 MR 研究中，没有证据表明 IBD 和这些细胞因子之间存在因果关系。
我们的研究表明 IL-17 和 MIG 与 IBD 之间存在潜在的因果关系。需要进一步的研究来确定 IL-17 和 MIG 或其下游效应物是否可用于 IBD 的管理。
