School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
The Fourth College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Front Immunol. 2022 Jul 5;13:886144. doi: 10.3389/fimmu.2022.886144. eCollection 2022.
Inflammation plays a pivotal role in the pathogenesis of cancer. Though previous studies have reported a link between several inflammatory biomarkers and risk of certain types of cancer, there is a lack of systematic investigation. Therefore, we aimed to assess the role of circulating cytokines on the risk of cancer using a two-sample Mendelian randomization (MR) approach.
We used genetic variants associated with circulating levels of cytokines from a meta-analysis of genome-wide association studies (GWASs) of 8,293 Finns as instrumental variables. Summary level data of 20 site-specific cancer were obtained from the UK BioBank including up to 456,348 participants of European ancestry. We performed two-sample MR analyses using inverse-variance weighted (IVW) method as the main method, followed by weighted-median and likelihood-based methods as sensitivity analysis. Pleiotropic and outlier variants were assessed by MR-Egger regression and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test.
224 genetic variants associated with 27 circulating cytokines achieving genome-wide significance (<5×10) were used as IVs. After Bonferroni correction, genetically predicted high levels of interleukin-18 (IL-18) were associated with a decreased risk of acute myeloid leukemia (odds ratio (OR) per 1 standard deviation (SD) increase = 0.55, 95% confidence interval (CI):0.43-0.69, =5.39×10), and circulating levels of IL-17 were associated with altered stomach cancer risk (OR per 1 SD increase = 0.15, 95% CI: 0.07-0.36, =1.25×10) by IVW. Results were stable across sensitivity analyses, and MR-Egger regression did not suggest the presence of directional pleiotropy. Additionally, we found suggestive evidence for 48 cytokine-cancer associations including tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and cutaneous T-cell attracting chemokine (CTACK) with the risk of several types of cancer (9.26×10≤<0.05).
By using a genetic epidemiological approach, our study systematically evaluated the role of circulating cytokines on the risk of cancer, and provided clues for potential therapeutic targets. However, the exact underlying biological mechanism warrants further investigation.
炎症在癌症发病机制中起着关键作用。尽管先前的研究报告了几种炎症生物标志物与某些类型癌症风险之间的联系，但缺乏系统的研究。因此，我们旨在使用两样本 Mendelian 随机化（MR）方法评估循环细胞因子在癌症风险中的作用。
我们使用来自 8293 名芬兰人的全基因组关联研究（GWAS）荟萃分析中与循环细胞因子水平相关的遗传变异作为工具变量。从 UK BioBank 中获得了 20 个特定部位癌症的汇总水平数据，其中包括多达 456348 名欧洲血统的参与者。我们使用逆方差加权（IVW）方法作为主要方法进行两样本 MR 分析，随后使用加权中位数和基于似然的方法进行敏感性分析。通过 MR-Egger 回归和 MR 偏倚 RESidual Sum and Outlier（MR-PRESSO）检验评估 pleiotropic 和异常值变异。
使用 224 种与 27 种循环细胞因子相关的遗传变异作为 IVs，这些变异达到了全基因组显着性（<5×10）。经过 Bonferroni 校正后，预测的高水平白细胞介素-18（IL-18）与急性髓系白血病风险降低相关（每增加 1 个标准差的比值比（OR）=0.55，95%置信区间（CI）：0.43-0.69，=5.39×10），而循环 IL-17 水平与胃癌风险改变相关（每增加 1 个标准差的 OR=0.15，95%CI：0.07-0.36，=1.25×10）。敏感性分析结果稳定，MR-Egger 回归未提示存在方向性偏倚。此外，我们发现了 48 种细胞因子-癌症关联的提示性证据，包括肿瘤坏死因子相关凋亡诱导配体（TRAIL）和皮肤 T 细胞吸引趋化因子（CTACK）与多种类型癌症的风险相关（9.26×10<0.05）。
通过使用遗传流行病学方法，我们系统地评估了循环细胞因子在癌症风险中的作用，并为潜在的治疗靶点提供了线索。然而，确切的潜在生物学机制需要进一步研究。
