Huang Xuanchun, Hu Lanshuo, Li Jun, Tao Shiyi, Xue Tiantian
Cardiology Department, Guang'anmen Hospital, China Academy of Traditional Chinese Medicine, Beijing, China.
Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Traditional Chinese Medicine, Beijing, China.
Front Cardiovasc Med. 2024 Dec 12;11:1378327. doi: 10.3389/fcvm.2024.1378327. eCollection 2024.
Inflammatory factors play a crucial role in the onset and progression of heart failure. To further explore the causal relationship between inflammatory factors and heart failure, we employed bidirectional Mendelian randomization analysis to investigate the causal links between 91 inflammatory cytokines and heart failure.
We conducted our study using the bidirectional Mendelian randomization approach. Data on 91 inflammatory factors were sourced from large-scale public genome-wide association study databases, while heart failure data were obtained from the FINNGEN database. The relationships between inflammatory factors and heart failure were evaluated using five methods: MR-Egger regression model, Inverse Variance Weighted method, Simple mode model, Weighted mode model, and Weighted median. Results were subjected to FDR multiple testing correction, and significant findings were discussed in detail. To enhance the robustness of our findings, various sensitivity analyses were conducted, including MR Egger intercept, MR-PRESSO and Cochran Q test.
Our forward Mendelian randomization study indicated that, of the 91 inflammatory factors examined, seven showed a causal relationship with heart failure. Four of these factors were significantly causally related to the incidence of heart failure: CXCL9 and IFN-γ as promotive factors, and LIFR and UPA as potential protective factors. Three inflammatory factors had a potential causal relationship with heart failure, with DNER as a potential protective factor, and MMP-1 and CD6 as potential promotive factors. Reverse Mendelian randomization suggested that the onset of heart failure might potentially influence the levels of four inflammatory factors, with ARTN and FGF5 decreasing after the onset of heart failure, and SLAM and MMP-10 increasing. Additionally, reliability tests of this Mendelian randomization, including MR-Egger intercept and MR-PRESSO tests, revealed no evidence of pleiotropy, and Cochran's Q test also confirmed the reliability of our results.
We identified CXCL9, IFN-γ, LIFR, and UPA as potential inflammatory factors associated with heart failure through forward Mendelian randomization. These findings suggest potential targets but require further validation.
炎症因子在心力衰竭的发生和发展中起关键作用。为进一步探讨炎症因子与心力衰竭之间的因果关系，我们采用双向孟德尔随机化分析来研究91种炎症细胞因子与心力衰竭之间的因果联系。
我们使用双向孟德尔随机化方法进行研究。91种炎症因子的数据来自大规模公共全基因组关联研究数据库，而心力衰竭数据则从芬兰基因组数据库（FINNGEN database）获得。使用五种方法评估炎症因子与心力衰竭之间的关系：MR-Egger回归模型、逆方差加权法、简单模式模型、加权模式模型和加权中位数法。对结果进行FDR多重检验校正，并对显著结果进行详细讨论。为提高研究结果的稳健性，我们进行了各种敏感性分析，包括MR Egger截距、MR-PRESSO和 Cochr an Q检验。
我们的正向孟德尔随机化研究表明，在所检测的91种炎症因子中，有7种与心力衰竭存在因果关系。其中4种因子与心力衰竭的发生率显著因果相关：CXCL9和IFN-γ为促进因子，LIFR和UPA为潜在保护因子。三种炎症因子与心力衰竭存在潜在因果关系，DNER为潜在保护因子，MMP-1和CD6为潜在促进因子。反向孟德尔随机化表明，心力衰竭的发生可能会影响四种炎症因子的水平，心力衰竭发生后ARTN和FGF5水平下降，而SLAM和MMP-10水平升高。此外，该孟德尔随机化的可靠性检验，包括MR-Egger截距和MR-PRESSO检验，均未发现多效性证据， Cochr an Q检验也证实了我们结果的可靠性。
通过正向孟德尔随机化，我们确定CXCL9、IFN-γ、LIFR和UPA为与心力衰竭相关的潜在炎症因子。这些发现提示了潜在靶点，但需要进一步验证。
