中国骨质疏松杂志

循环炎症细胞因子与骨质疏松症的双向孟德尔随机化研究

A bidirectional Mendelian randomization study on the causal relationship between circulating inflammatory cytokines and osteoporosis

DOI：10.3969/j.issn.1006-7108.2025.01.012

中文关键词: 骨质疏松症孟德尔随机化炎症因子流行病学因果关系

英文关键词:osteoporosis Mendelian randomization inflammatory cytokine epidemiology causal inference

基金项目:中国博士后科学基金面上项目（2023M731070）；湖南省临床医疗技术创新引导项目（2021SK51301）；湖南中医药大学研究生创新课题立项项目（2022CX41）

作者	单位
匡昱林1，2，3 匡浩铭1，2，3 李洪芳4 熊罗节5 龚智超3 欧梁1 孙绍裘2，3*	1.湖南省中医药研究院，湖南长沙 410013 2.湖南中医药大学，湖南长沙 410208 3.湖南中医药大学第二附属医院，湖南长沙 410005 4.遵义医科大学附属医院，贵州遵义 563000 5.浙江中医药大学附属第一医院，浙江杭州 310006

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中文摘要:

目的运用双向孟德尔随机化（mendelian randomization，MR）方法系统评估循环炎症细胞因子与骨质疏松症（osteoporosis，OP）的因果关系。方法从全基因组关联研究（genome-wide association studies，GWAS）中获取91种炎症细胞因子和OP的遗传相关数据。采用多种双样本MR方法估计因果效应，包括逆方差加权法（inverse-variance weighting，IVW）、MR-Egger回归、加权中位数法和模式法。使用Cochran's Q检验、MR-Egger截距项和MR-PRESSO评估异质性和多效性。结果 IVW方法鉴定出5种与OP风险显著相关的细胞因子：CXCL1（OR=1.100，P=0.020）、CXCL11（OR=1.150，P=0.005）、IL-18（OR=1.087，P=0.012）、TNF（OR=1.108，P=0.014）为危险因素，而ARTN（OR=0.895，P=0.015）为保护因素。敏感性分析支持这些因果关联。反向MR表明，OP可能导致FGF21的循环水平降低（β=-0.076，P=0.003）。结论本研究提供遗传学证据，表明CXCL1、CXCL11、IL-18和TNF可能是OP的危险因素，而ARTN可能是一个新的保护因子。此外，OP本身可能通过抑制FGF21分泌而加重骨丢失。这些发现为OP的发病机制和潜在干预靶点提供了新的见解。

英文摘要:

Objective To systematically assess the potential causal relationship between circulating inflammatory cytokines and osteoporosis (OP) using a bidirectional Mendelian randomization (MR) approach. Methods Genetic association data for 91 inflammatory cytokines and OP were obtained from genome-wide association studies (GWAS). The causal effects were estimated using several two-sample MR methods, including inverse-variance weighted (IVW), MR-Egger regression, weighted median, and mode-based methods. Heterogeneity and pleiotropy were assessed using Cochran's Q test, MR-Egger intercept, and MR-PRESSO. Results The IVW method identified five cytokines significantly associated with OP risk: CXCL1 (OR=1.100, P=0.020), CXCL11 (OR=1.150, P=0.005), IL-18 (OR=1.087, P=0.012), TNF (OR=1.108, P=0.014) as risk factors, and ARTN (OR=0.895, P=0.015) as a protective factor. Sensitivity analyses supported these causal associations. Interestingly, OP was found to potentially reduce the circulating level of FGF21 (β=-0.076, P=0.003). Conclusion This study provides genetic evidence that CXCL1, CXCL11, IL-18, and TNF may causally increase the risk of OP, while ARTN may be a novel protective factor. Moreover, OP itself may aggravate bone loss by suppressing FGF21 secretion. These findings offer new insights into the pathogenesis of OP and potential intervention targets for its prevention and treatment.

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