中国组织工程研究

中国组织工程研究 ›› 2025, Vol. 29 ›› Issue (8): 1556-1564.doi: 10.12307/2025.322

• 骨组织构建 bone tissue construction • 上一篇    下一篇

两样本孟德尔随机化分析循环炎症细胞因子与骨密度的因果关联

陈  帅，金  杰，韩化伟，田宁晟，李志伟   

  1. 南京中医药大学第二附属医院(江苏省第二中医院)骨伤科，江苏省南京市  210017
  • 收稿日期:2024-01-19 接受日期:2024-04-19 出版日期:2025-03-18 发布日期:2024-07-05
  • 通讯作者: 李志伟，教授，主任医师，硕士生导师，南京中医药大学第二附属医院(江苏省第二中医院)骨伤科，江苏省南京市 210017
  • 作者简介:陈帅，男，1998年生，江苏省扬州市人，汉族，南京中医药大学在读硕士，主要从事脊柱疾病的防治研究。
  • 基金资助:
    江苏省科技计划专项资金重点研发计划社会发展项目(BE2023787)，项目负责人：李志伟；江苏省卫生健康委员会老年健康科研项目(LKZ2022008)，项目负责人：李志伟

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

Chen Shuai, Jin Jie, Han Huawei, Tian Ningsheng, Li Zhiwei    

  1. Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing 210017, Jiangsu Province, China
  • Received:2024-01-19 Accepted:2024-04-19 Online:2025-03-18 Published:2024-07-05
  • Contact: Li Zhiwei, Professor, Chief physician, Master’s supervisor, Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing 210017, Jiangsu Province, China
  • About author:Chen Shuai, Master candidate, Department of Orthopaedics, The Second Affiliated Hospital of Nanjing University of Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing 210017, Jiangsu Province, China
  • Supported by:
    Jiangsu Provincial Science and Technology Plan Special Fund for Key Social R&D Plan Project, No. BE2023787 (to LZW); the Elderly Health Research Project of Jiangsu Commission of Health, No. LKZ2022008 (to LZW)

PDF

24

摘要：


文题释义：
骨质疏松：是以骨量低下、骨微结构破坏导致骨脆性增加、易发生骨折为特征的一种全身性骨骼疾病。
孟德尔随机化：是一种利用遗传变异作为工具变量，来探索暴露(例如风险因素或干预措施)与结果(例如疾病或测量结果)之间因果关系的分析方法。这种方法有助于解决观察性研究中可能存在的混杂和反向因果关系的问题，提供更接近因果推断的结果。

背景：最近许多研究表明，炎症细胞因子与骨质疏松症和骨密度之间存在密切关系，然而炎症细胞因子与骨密度之间的因果关系尚未完全揭示。
目的：采用两样本孟德尔随机化方法探究炎症细胞因子与骨密度之间潜在的因果关系。
方法：从全基因组关联研究(GWAS)公开数据库中筛选出与41种循环炎症细胞因子相关的单核苷酸多态性作为工具变量。骨密度的GWAS汇总数据来自骨质疏松症遗传因素联盟(GEFOS)，共涉及32 735名欧洲血统的个体。逆方差加权法作为主要的分析方法来评估因果效应，加权中位数法、MR Egger回归法、简单中位数法和加权中值方法用于补充说明。利用MR-Egger Intercept和MR-PRESSO分析方法进行多效性检验，采用Cochran’s Q检验结果是否存在异质性，同时使用留一法评估结果的稳定性。另外，为了更准确地评估因果关系，采用Bonferroni校正来确定与骨密度有强因果关系的炎症细胞因子。
结果与结论：①逆方差加权法分析结果显示，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)，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)，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)，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)，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)，白细胞介素5、基质衍生因子1a、肝细胞生长因子、白细胞介素4与足跟骨密度之间存在负向因果效应(β=-0.019，95%CI：-0.031至-0.006，P=0.004；β=-0.022，95%CI：-0.038至-0.005，P=0.010；β=-0.021，95%CI：-0.041至-0.002，P=0.030；β=-0.016，95%CI：-0.032至-0.001，P=0.034)，神经生长因子、粒细胞集落刺激因子与足跟骨密度之间存在正向因果关系(β=0.019，95%CI：0.002-0.036，P=0.033；β=0.011，95%CI：0.000-0.022，P=0.050)；经Bonferroni校正后发现，白细胞介素8与腰椎骨密度之间有强正向因果效应(P=0.000 5)。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。②敏感性分析结果显示，循环炎症细胞因子对骨密度的因果效应没有异质性、多效性或异常值。

关键词: 骨质疏松, 骨密度, 炎症细胞因子, 孟德尔随机化, 因果关系

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

中图分类号: