Zheng Haoran, Mao Xinxin, Fu Zhenyue, Chen Chunmei, Lv Jiayu, Wang Yajiao, Wang Yuxin, Wu Huaqin, Li Yvmeng, Tan Yong, Gao Xiya, Zhao Lu, Xu Xia, Zhang Bingxuan, Song Qingqiao
General Internal Medicine Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
Front Cardiovasc Med. 2024 Oct 22;11:1332015. doi: 10.3389/fcvm.2024.1332015. eCollection 2024.
Cytokines play a pivotal role in the progression of heart failure (HF) by modulating inflammatory responses, promoting vasoconstriction, and facilitating endothelial injury. However, it is now difficult to distinguish the causal relationship between HF and cytokines in observational studies. Mendelian randomization (MR) analyses of cytokines probably could enhance our comprehension to the underlying biological processes of HF.
This study was to explore the correlation between 41 cytokines with HF at the genetic level by MR analysis. We selected a HF dataset from the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) 2018 and a cytokine dataset from a meta-analysis of cytokine levels in Finns. Two-sample, bidirectional MR analyses were performed using Inverse Variance Weighted (IVW), Weighted Median and MR- egger, and the results were tested for heterogeneity and pleiotropy, followed by sensitivity analysis.
Genetic prediction of high levels of circulating Macrophage inflammatory pro-tein-1β(MIP-1β) ( = 0.0389), Interferon gamma induced protein 10(IP-10) ( = 0.0029), and Regu-lated on activation, normal T cell expressed and secreted(RANTES) ( = 0.0120) expression was associated with an elevated risk of HF. HF was associated with the increased levels of circulating Interleukin-2 receptor, alpha subunit(IL-2ra) ( = 0.0296), Beta nerve growth fac-tor(β-NGF) ( = 0.0446), Interleukin-17(IL-17) ( = 0.0360), Basic fibroblast growth factor(FGF-basic) ( = 0.0220), Platelet derived growth factor BB(PDGF-BB) ( = 0.0466), and Interferon-gamma(IFN-) ( = 0.0222); and with decreased levels of Eotaxin ( = 0.0133). The heterogeneity and pleiotropy of the cytokines were acceptable, except for minor heterogeneity of FGF-basic and IL-17.
These findings provide compelling evidence for a genetically predictive relationship between cytokines and HF, emphasizing a great potential of targeted modulation of cytokines in slowing the progression of HF. This study draws further conclusions at the genetic level, providing a basis for future large-scale clinical trials.
细胞因子通过调节炎症反应、促进血管收缩和加重内皮损伤，在心力衰竭（HF）进展中起关键作用。然而，在观察性研究中，目前很难区分HF与细胞因子之间的因果关系。对细胞因子进行孟德尔随机化（MR）分析可能会增强我们对HF潜在生物学过程的理解。
本研究旨在通过MR分析在基因水平上探索41种细胞因子与HF之间的相关性。我们从心力衰竭分子流行病学治疗靶点（HERMES）2018中选取了一个HF数据集，并从芬兰人细胞因子水平的荟萃分析中选取了一个细胞因子数据集。使用逆方差加权（IVW）、加权中位数和MR-egger进行双样本双向MR分析，并对结果进行异质性和多效性检验，随后进行敏感性分析。
循环中高水平的巨噬细胞炎性蛋白-1β（MIP-1β）（=0.0389）、干扰素γ诱导蛋白10（IP-10）（=0.0029）和调节激活正常T细胞表达和分泌因子（RANTES）（=0.0120）的基因预测与HF风险升高相关。HF与循环中白细胞介素-2受体α亚基（IL-2ra）（=0.0296）、β神经生长因子（β-NGF）（=0.0446）、白细胞介素-17（IL-17）（=0.0360）、碱性成纤维细胞生长因子（FGF-basic）（=0.0220）、血小板衍生生长因子BB（PDGF-BB）（=0.0466）和干扰素-γ（IFN-）（=0.0222）水平升高相关；与嗜酸性粒细胞趋化因子水平降低（=0.0133）相关。除FGF-basic和IL-17存在轻微异质性外，细胞因子的异质性和多效性均可接受。
这些发现为细胞因子与HF之间的基因预测关系提供了有力证据，强调了靶向调节细胞因子在减缓HF进展方面的巨大潜力。本研究在基因水平上得出了进一步结论，为未来大规模临床试验提供了依据。
