Exploring the causal relationship between rheumatoid arthritis and coronary atherosclerosis: a Mendel randomized study involving serum metabolites and inflammatory factors

Abstract

Abstract: BACKGROUND: The relationship between rheumatoid arthritis and coronary atherosclerosis has received extensive attention, but observational studies have not yet clarified the causal relationship. The changes in inflammatory markers and serum metabolites are closely related to various human diseases. Research shows that inflammation is related to rheumatoid arthritis and coronary atherosclerosis, indicating that there may be a common pathophysiological pathway between the two diseases.
OBJECTIVE: This study explored whether there was a causal relationship between rheumatoid arthritis and coronary atherosclerosis, as well as the potential causal relationship with 1400 serum metabolites and 91 inflammatory factors through Mendelian randomization analysis.
METHODS: Coronary atherosclerosis data is from Finngen database, rheumatoid arthritis data is from IEU OpenGWAS database, serum metabolites data is from Canadian Longitudinal Study on Aging, Augsburg Cooperative Health Research and British Twin Project Research, and 91 inflammatory proteins data is from research published in Nature Immunology in 2023. Perform Mendelian randomization analysis using data from genome-wide association studies, and evaluate causal effects using inverse variance weighting, MR Egger regression, weighted median, weighted model, and simple model methods, with IVW being the primary analysis method. To enhance robustness, Cochran's Q-test MR Egger intercept was used for sensitivity analysis.
RESULTS AND CONCLUSION: IVW results showed that rheumatoid arthritis was positively correlated with the increased relative risk of coronary atherosclerosis (OR=1.002, 95% CI=1.001-1.003, P=0.003); There is 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 is a causal relationship between 51 serum metabolites and 7 inflammatory factors and rheumatoid arthritis. This study provides epidemiological evidence between rheumatoid arthritis and coronary atherosclerosis, and emphasizes 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.

Key words: Rheumatoid arthritis, Coronary atherosclerosis, Serum metabolites, Inflammatory factors, Mendelian randomization analysis

CLC Number:

Zhang Yibo, Lu Jianqi, Mao Meiling, Pang Yan, Dong Li, Yang Shangbing, Xiao Xiang. Exploring the causal relationship between rheumatoid arthritis and coronary atherosclerosis: a Mendel randomized study involving serum metabolites and inflammatory factors[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(在线): 1-9.

Figures/Tables 9

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= 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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