Rheumatoid arthritis and coronary atherosclerosis: data analysis of serum metabolite and inflammatory factor in the European population

doi:10.12307/2025.758

Abstract

Abstract: BACKGROUND: The relationship between rheumatoid arthritis and coronary atherosclerosis has received extensive attention. Inflammation is related to rheumatoid arthritis and coronary atherosclerosis, indicating that there may be a common pathophysiological pathway between the two diseases. However, observational studies have not yet clarified the causal relationship.
OBJECTIVE: To explore whether there is a causal relationship between rheumatoid arthritis and coronary atherosclerosis, as well as the potential causal relationship with 1 400 serum metabolites and 91 inflammatory factors through a Mendelian randomization analysis.
METHODS: Coronary atherosclerosis data are from Finngen database, rheumatoid arthritis data are from IEU OpenGWAS database, serum metabolites data are from Canadian Longitudinal Study on Aging, Augsburg Cooperative Health Research and British Twin Project Research, and data of 91 inflammatory proteins are from research published in Nature Immunology in 2023. Mendelian randomization analysis was performed using data from genome-wide association studies, and causal effects were evaluated using inverse variance weighting, MR-Egger regression, weighted median, weighted model, and simple model methods, with inverse variance weighting being the primary analysis method. To enhance robustness, Cochran’s Q-test MR-Egger intercept was used for sensitivity analysis.
RESULTS AND CONCLUSION: (1) Inverse variance weighting results showed that rheumatoid arthritis was positively correlated with the increased relative risk of coronary atherosclerosis (odds ratio=1.002, 95% confidence interval=1.001-1.003, P=0.003). There was no reverse causal relationship between coronary atherosclerosis and rheumatoid arthritis. In addition, 96 serum metabolites and 9 inflammatory factors were found to have causal relationships with coronary atherosclerosis. There was a causal relationship between 51 serum metabolites and 7 inflammatory factors and rheumatoid arthritis. (2) This study provided epidemiological evidence between rheumatoid arthritis and coronary atherosclerosis, and emphasized the potential role of serum metabolites and inflammatory factors in the pathogenesis of these diseases. These findings may contribute to the development of new treatment strategies. Due to the limited inclusion of data from Asian populations, most contemporary studies used international databases and European population analyses. By collecting and analyzing the health data of European populations, it is conducive to a better understanding of the effects and potential role of Chinese medicine in Europe, and to further promote the practice of modern integration of Western and Chinese medicine. Meanwhile, through the comparative study with the European databases, it is possible to reveal the genetic differences and susceptibility to diseases among different populations, providing more dimensions and perspectives for global health research.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: rheumatoid arthritis, coronary atherosclerosis, serum metabolites, inflammatory factors, causality, Mendelian randomization analysis, engineered tissue construction

CLC Number:

Zhang Yibo, Lu Jianqi, Mao Meiling, Pang Yan, Dong Li, Yang Shangbing, Xiao Xiang. Rheumatoid arthritis and coronary atherosclerosis: data analysis of serum metabolite and inflammatory factor in the European population[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(24): 5263-5271.

Figures/Tables 6

2.1 工具变量最初提取与类风湿关节炎和冠状动脉粥样硬化相关的所有单核苷酸多态性，然后根据工具变量的特定标准进行筛选，排除潜在的数据偏差，最终54个单核苷酸多态性被纳入工具变量。以血清代谢物作为暴露，确定了33 421个与冠状动脉粥样硬化相关的单核苷酸多态性和32 268个与类风湿关节炎相关的单核苷酸多态性关于炎症因子，选择了2 695个与冠状动脉粥样硬化相关的单核苷酸多态性和2 719个与抑郁症相关的单核苷酸多态性。 2.2 孟德尔随机化分析结果 2.2.1 类风湿关节炎与冠状动脉粥样硬化的相关性类风湿关节炎与冠状动脉粥样硬化相关性的孟德尔随机化结果，见图1所示。逆方差加权分析结果表明，类风湿关节炎是冠状动脉粥样硬化易感性的危险因素(OR=1.002，95%CI=1.001-1.003，P=0.003)，加权中位数法(OR=1.003，95%CI= 1.001-1.004，P=0.014)、MR-Egger方法(OR=1.003，95%CI=1.001-1.005，P= 0.029)分析结果也表明类风湿关节炎是冠状动脉粥样硬化易感性的危险因素。另外还进行了反向孟德尔随机化研究，以探讨冠状动脉粥样硬化与类风湿关节炎之间是否存在相关性，逆方差加权分析结果表明，冠状动脉粥样硬化对类风湿关节炎没有潜在的因果影响(OR=1.001，95%CI=0.977-1.026，P=0.939)，见表2。 2.2.2 血清代谢物与冠状动脉粥样硬化的相关性逆方差加权分析结果表明，42种血清代谢物(如对精氨酸与谷氨酸的比例)(P=0.006，OR=0.996，95%CI=0.994-0.999)可能与冠状动脉粥样硬化风险呈负相关，54种血清代谢物(如对甲酚硫酸盐含量)(P= 8.28×10-5，OR=11.005，95%CI=1.003-1.008)与冠状动脉粥样硬化风险正相关，见图2。 2.2.3 炎症蛋白与冠状动脉粥样硬化的相关性逆方差加权分析结果表明，9种炎症因子与冠状动脉粥样硬化之间存在因果关系，其中成纤维细胞生长因子5(P=0.003，OR=1.004，95%CI=1.001-1.006)、肝细胞生长因子(P=0.014，OR=1.003，95%CI=1.001-1.006)、Fms相关酪氨酸激酶3配体(P=0.014，OR=1.003，95%CI=1.001-1.005)、C-C基序趋化因子28 (P=0.021，OR=1.003，95%CI=1.000-1.006)、C-C基序趋化因子4 (P=0.021，OR=1.003，95%CI=1.000-1.006)、抑瘤素M(P=0.031，OR=1.004，95%CI=1.000-1.008)水平可增加冠状动脉粥样硬化患病风险；白细胞介素6 (P=0.006，OR=0.995，95%CI=0.991-0.998)、白细胞介素5 (P=0.010，OR=0.996，95%CI=0.992-0.999)、青蒿素(P=0.050，OR=0.998，95%CI=0.995-0.100)水平可在基因水平上降低冠状动脉粥样硬化患病风险，见图3。 2.2.4 血清代谢物与类风湿关节炎的相关性逆方差加权分析结果表明，29种血清代谢物(如琥珀酸盐水平，P=0.006，OR=0.998，95%CI=0.997-0.100)可能与类风湿关节炎风险呈负相关；相反，22种血清代谢物(如胱硫醚水平，P=0.001，OR=1.002，95%CI=1.001-1.003)与类风湿关节炎风险正相关，见图4。"

2.2.5 炎症蛋白与类风湿关节炎的相关性逆方差加权分析结果表明，7种炎症因子与类风湿关节炎之间存在因果关系，见图5。其中，4种炎症因子与类风湿关节炎之间呈负向因果关系，白细胞介素6(P=0.012，OR=0.998，95%CI=0.996-0.100)、C-C基序趋化因子19(P=0.026，OR=0.998，95%CI= 0.997-0.100)、神经生长因子(P=0.012，OR=0.998，95%CI=0.997-0.100)、C-C基序趋化因子4(P=0.018，OR=0.999，95%CI=0.998-0.100)水平与类风湿关节炎之间呈负相关。CD40L受体(P=0.032，OR=1.001，95%CI=1.000-1.002)、程序性细胞死亡1配体1(P=0.021，OR=1.002，95%CI=1.000-1.003)、C-X-C基序趋化因子10(P=0.015，OR=1.002，95%CI= 1.000-1.003)水平与类风湿关节炎之间呈正相关。 2.3 敏感性分析结果 2.3.1 类风湿关节炎与冠状动脉粥样硬化相关性的敏感性分析结果采用MR-Egger法的截距项对水平多效性进行评估，结果显示类风湿关节炎与冠状动脉粥样硬化相关性的孟德尔随机化分析中未获得水平多效性的证据(P=0.247，MR-Egger截距=0.201)。敏感性Cochran’s Q检验结果表明，类风湿关节炎与冠状动脉粥样硬化相关性的孟德尔随机化分析中不存在异质性(基于逆方差加权法P= 0.059、Q=34.167，基于MR-Egger法P=0.074，Q=49.842)，见表2。反向孟德尔随机化分析结果显示，冠状动脉粥样硬化与类风湿关节炎相关性的孟德尔随机化分析中未获得水平多效性的证据(P=0.585，MR-Egger截距=7.39×10-5)。敏感性Cochran’s Q 检验结果表明，冠状动脉粥样硬化与类风湿关节炎相关性的孟德尔随机化分析中不存在异质性(基于逆方差加权法P=0.108、Q=37.488，基于MR-Egger法P=0.094、Q=37.069)，见表2。通过留一法逐个剔除，未见明显影响结果的单核苷酸多态性，见图6。漏斗图显示代表因果关系的效应点呈对称分布，见图7，表示受潜在偏倚影响的可能性较少；此外，散点图(图8)和漏斗图排除了潜在异常值和水平多效性的可能性。敏感性分析进一步"

排除了异质性和水平多效性的影响，证明了结果的稳健性。 2.3.2 血清代谢物与冠状动脉粥样硬化相关性的敏感性分析结果采用MR-Egger法的截距项对水平多效性进行评估，结果显示鞘磷脂(P=0.029，MR-Egger截距=0.002)、二十二碳六烯酸DHA(P=0.036，MR-Egger截距=-0.001)、1-硬脂酰基-2-吲哚甲酰基-GPI (P=0.036，MR-Egger截距= 0.001)、N-乙酰基异嘌呤(P=0.039，MR-Egger截距=-0.001)、N-乙酰牛磺酸(P=0.040，MR-Egger截距=-0.001)水平存在潜在水平多效性，其余血清代谢物均不存在水平多效性。敏感性Cochran’s Q 检验结果表明，27种代谢物存在异质性(基于逆方差加权法P < 0.05)，其余69种代谢物不存在异质性，表明所选工具变量具有可靠性。 2.3.3 炎症蛋白与冠状动脉粥样硬化相关性的敏感性分析结果采用MR-Egger法的截距项对水平多效性进行评估，未发现水平多效性的存在。敏感性Cochran’s Q 检验结果表明，成纤维细胞生长因子5(基于逆方差加权法P=3.03×10-8、Q=95.546，基于MR-Egger 法P=1.71×10-8、Q=95.505)、抑瘤素M(基于逆方差加权法 P= 0.010、Q=42.879，基于MR-Egger法 P=0.011、Q=41.408)、Fms相关酪氨酸激酶3配体(基于逆方差加权法P= 0.045、Q=61.090，基于MR-Egger法P=0.043、Q=60.198)水平存在异质性，仅有3种炎症蛋白存在潜在异质性，表明结果仍具有稳健性。 2.3.4 血清代谢物与类风湿关节炎相关性的敏感性分析结果采用MR-Egger法的截距项对水平多效性进行评估，结果显示2-甲氧基间苯二酚硫酸盐含量(P=0.009，MR-Egger截距=-0.000)、1-硬脂酰基-2-油酰基-GPI(P=0.018，MR-Egger截距=-0.001)、胱氨酸(P=0.032，MR-Egger截距= 0.000)、5-α-孕烷-3-β，2-β二醇单硫酸盐1(P=0.038，MR-Egger截距= 0.000)水平存在潜在水平多效性，其余血清代谢物均不存在水平多效性。敏感性Cochran’s Q检验结果表明，3-(4-羟基苯基)乳酸(基于逆方差加权法P=0.016、Q=41.188，基于MR-Egger法 P=0.013、Q=40.750)、1-硬脂酰-2-油酰基-GPI(基于逆方差加权法P=0.016、Q=41.188，基于法MR-Egger P=0.122、Q=27.497)水平存在异质性，其余血清代谢物均不存在异质性，证明了结果的可靠性。 2.3.5 炎症蛋白与类风湿关节炎相关性的敏感性分析结果采用MR-Egger法的截距项对水平多效性进行评估，程序性细胞死亡1配体1 (P=0.050，MR-Egger截距=-0.000)水平存在潜在水平多效性，其余炎症蛋白均不存在水平多效性。敏感性Cochran’s Q检验结果表明，C-C基序趋化因子19(基于逆方差加权法 P=8.36×10-8、Q=99.094，基于MR-Egger法P=3.06×10-7、Q=93.584)、C-C基序趋化因子10(基于逆方差加权法P=0.001、Q=61.901，基于MR-Egger法P=0.001、Q=60.594)、C-C基序趋化因子4(基于逆方差加权法P=0.005、Q=56.294，基于MR-Egger法P=0.004、Q=56.244)水平存在异质性，程序性细胞死亡1配体1、白细胞介素6、CD40L受体、神经生长因子水平均不存在显著的异质性。"

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