Causal relationship between circulating inflammatory cytokines and bone mineral density based on two-sample Mendelian randomization

doi:10.12307/2025.322

Abstract

Abstract: BACKGROUND: Many recent studies have shown a close relationship between inflammatory cytokines and osteoporosis and bone mineral density (BMD). However, the causal relationship between inflammatory cytokines and BMD has not been fully revealed.
OBJECTIVE: To explore the potential causal relationship between inflammatory cytokines and BMD using a two-sample Mendelian randomization analysis.
METHODS: The single nucleotide polymorphisms associated with 41 circulating inflammatory cytokines were selected from the open database of genome-wide association studies (GWAS) as instrumental variables. The GWAS data about BMD were from the Genetic Factors for Osteoporosis Consortium, involving a total of 32 735 individuals of European ancestry. Inverse variance weighting was used as the primary analysis to evaluate the causal effect. Weighted median, MR Egger regression, simple mode, and weighted mode methods were used to supplement the explanation. We used the MR-Egger intercept and MR-PRESSO method to conduct a pleiotropy test, the Cochran’s Q test was used to determine whether there was heterogeneity in the results, and the leave-one-out method was used to evaluate the stability of the results. In addition, to more accurately assess the causality, the Bonferroni-corrected test was used to identify inflammatory cytokines that have a strong causal relationship with BMD.
RESULTS AND CONCLUSION: (1) According to the results of the inverse variance weighting method, we found a positive causal relationship between interleukin-8 and lumbar spine BMD [β=0.075, 95% confidence interval (CI): 0.033-0.117, P=0.000 5), while a negative causal relationship between interleukin-17 and lumbar spine BMD (β=-0.083, 95% CI: -0.152 to -0.014, P=0.018). There might be a negative causal relationship between tumor necrosis factor b and femoral neck BMD (β=-0.053, 95% CI: -0.088 to -0.018, P=0.003), while a positive causal relationship between basic fibroblast growth factor and femoral neck BMD (β=0.085, 95% CI: 0.016-0.154, P=0.015). There might be a negative causal relationship between macrophage inflammatory protein-1a and total body BMD (β=-0.056, 95% CI: -0.105 to -0.007, P=0.025). There was a negative causal relationship between interleukin-5 (β=-0.019, 95% CI: -0.031 to -0.006, P=0.004), stromal cell-derived factor-1a (β=-0.022, 95% CI: -0.038 to -0.005, P=0.010), hepatocyte growth factor (β=-0.021, 95% CI: -0.041 to -0.002, P=0.030), interleukin-4 (β=-0.016, 95% CI: -0.032 to -0.001, P=0.034) and heel BMD, while a positive causal relationship between nerve growth factor (β=0.019, 95% CI: 0.002-0.036, P=0.033), granulocyte colony-stimulating factor (β=0.011, 95% CI: 0.000-0.022, P=0.050), and heel BMD. Meanwhile, after the Bonferroni-corrected test, there was a strong positive causal effect between interleukin-8 and lumbar spine BMD (P=0.000 5). And consistent directional effects for all analyses were observed in MR Egger, weighted median, simple mode, and weighted mode methods. (2) Sensitivity analyses revealed no heterogeneity, pleiotropy, or outliers for the causal effect of circulating inflammatory cytokines on BMD.

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: osteoporosis, bone mineral density, inflammatory cytokine, Mendelian randomization, causality

CLC Number:

Chen Shuai, Jin Jie, Han Huawei, Tian Ningsheng, Li Zhiwei . Causal relationship between circulating inflammatory cytokines and bone mineral density based on two-sample Mendelian randomization [J]. Chinese Journal of Tissue Engineering Research, 2025, 29(8): 1556-1564.

Figures/Tables 7

2.2 循环炎症细胞因子与腰椎骨密度的因果关系 IVW法分析结果显示，遗传预测的白细胞介素8与腰椎骨密度之间呈正向因果关系(β=0.075，95%CI：0.033-0.117，P=0.000 5)；而遗传预测的白细胞介素17与腰椎骨密度之间呈负向因果关系(β=-0.083，95%CI：-0.152至-0.014，P=0.018)。同时经Bonferroni校正后发现，白细胞介素8与腰椎骨密度之间存在强因果关系(表2)。此外，MR-Egger法、加权中位数法、简单中位数法和加权中值法分析结果方向一致，见图2。 2.3 循环炎症细胞因子与股骨颈骨密度、前臂骨密度的因果关系 IVW法分析结果显示，遗传预测的肿瘤坏死因子b与股骨颈骨密度之间可能存在负向因果效应(β=-0.053，95%CI：-0.088至-0.018，P=0.003)，遗传预测的碱性成纤维细胞生长因子与股骨颈骨密度之间可能存在正向因果关系(β=0.085，95%CI：0.016-0.154，P=0.015)(表2)。并且MR-Egger法、加权中位数法、简单中位数法和加权中值法分析结果方向一致(图2)。此外根据IVW法分析结果，未发现遗传预测的循环炎症细胞因子与前臂骨密度之间存在因果关系。 2.4 循环炎症细胞因子与全身骨密度的因果关系 IVW法分析结果显示，遗传预测的巨噬细胞炎症蛋白1a与全身骨密度之间可能存在负向因果效应(β=-0.056，95%CI：-0.105至-0.007，P=0.025)(表2)。并且MR-Egger法、加权中位数法、简单中位数法和加权中值法分析结果方向一致(图2)。 2.5 循环炎症细胞因子与足跟骨密度的因果关系 IVW法分析结果显示，遗传预测的白细胞介素5(β=-0.019，95%CI：-0.031至-0.006，P=0.004)、基质衍生因子1a(β=-0.022，95%CI：-0.038至-0.005，P=0.010)、肝细胞生长因子(β=-0.021，95%CI：-0.041至-0.002，P=0.030)、白细胞介素4(β=-0.016，95%CI：-0.032至-0.001，P=0.034)与足跟骨密度之间存在负向因果效应；遗传预测的神经生长因子(β=0.019，95%CI：0.002-0.036，P=0.033)、粒细胞集落刺激因子(β=0.011，95%CI：0.000-0.022，P=0.050)与足跟骨密度之间存在正向因果关系(表2)。并且MR-Egger法、加权中位数法、简单中位数法和加权中值法分析结果方向一致(图2)。 2.6 敏感性分析研究进行了一系列敏感性分析，以检验结果是否存在异质性和水平多效性(表 3)。根据Cochran’s Q检验结果，没有观察到显著的异质性(P > 0.05)。同时，MR-Egger回归的截距均接近于0且检验P值均 > 0.05，表示结果不存在水平多效性。此外留一法检验分析显示，在逐个剔除单核苷酸多态性后结果相对稳定，无单核苷酸多态性对因果关系具有较大影响，见图3。"

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