炎症蛋白与骨质疏松症的遗传因果推断及免疫细胞表型的中介效应分析*

doi:10.3870/j.issn.1672-0741.25.08.010

摘要/Abstract

摘要： 目的利用两步双样本孟德尔随机化方法探究免疫细胞介导下炎症蛋白与骨质疏松症的因果关系。方法本研究采用孟德尔随机化方法,将已发表的大规模全基因组关联研究的91种炎症蛋白作为暴露因素,731种免疫细胞表型作为潜在的中介变量,骨质疏松症作为结局因素,探讨三者之间的因果关系,并探究免疫细胞在炎症蛋白影响骨质疏松症发展途径中的介导作用。以逆方差加权作为主要统计方法,并辅以多层级敏感性分析以加强结果的稳定性。结果逆方差加权法分析结果显示,4种炎症蛋白与骨质疏松症存在显著相关性,且4种炎症蛋白与骨质疏松症风险呈正相关;48种免疫细胞与骨质疏松症存在显著相关性,其中29种免疫细胞与骨质疏松症风险呈正相关,19种免疫细胞与骨质疏松症风险呈负相关。反向孟德尔随机化分析未发现显著相关性。敏感性分析未发现显著的异质性和水平多效性。此外,中介分析结果显示,BAFF-R on IgD^-CD38br部分介导了神经鞘胚素(Artemin,ARTN)(β=0.051,OR=1.053,P=0.002)与骨质疏松症的因果效应,中介效应为0.002,中介占比为3.9%,直接效应为0.049。结论孟德尔随机化分析为炎症蛋白与骨质疏松症之间的双向因果关系提供了支持证据,确定了ARTN可能通过增加BAFF-R on IgD^- CD38br水平导致骨质疏松症的发生。

关键词: 骨质疏松症, 炎症蛋白, 免疫细胞, 孟德尔随机化, 中介分析

Abstract: Objective To investigate the causal relationships between inflammatory proteins,immune cell-mediated pathways,and osteoporosis using a two-step two-sample Mendelian randomization(MR)approach. Methods This MR study leveraged large-scale genome-wide association studies(GWAS)to analyze 91 inflammatory proteins as exposures,731 immune cell phenotypes as potential mediators,and osteoporosis as the outcome.Inverse variance weighted(IVW)regression served as the primary statistical method,complemented by multilayered sensitivity analyses to enhance robustness. Results The inverse variance weighted method showed that four inflammatory proteins were significantly associated with osteoporosis,all exhibiting positive correlations with disease risk.Among 48 immune cell phenotypes significantly linked to osteoporosis,29 showed positive associations,and 19 showed negative associations with disease risk.Reverse Mendelian randomization analysis revealed no significant correlations,and sensitivity analyses identified no evidence of substantial heterogeneity or horizontal pleiotropy.Furthermore,mediation analysis demonstrated that BAFF-R on IgD^-CD38br partially mediated the causal effect between ARTN(β=0.051,OR=1.053,P=0.002)and osteoporosis.The mediation effect was 0.002,the mediating proportion was 3.9%,and the direct effect was 0.049. Conclusion Mendelian randomization analysis provided supporting evidence for bidirectional causal relationships between inflammatory proteins and osteoporosis,identifying that ARTN may drive osteoporosis development via increasing BAFF-R on IgD^-CD38br.

Key words: osteoporosis, inflammatory protein, immune cell, Mendelian randomization, mediation analysis

中图分类号:

R681.4

饶豪, 吴刚, 张旭兴, 何苗, 周毅, 胡翔宇. 炎症蛋白与骨质疏松症的遗传因果推断及免疫细胞表型的中介效应分析^*[J]. 华中科技大学学报（医学版）, 2026, 55(2): 204-213.

Rao Hao, Wu Gang, Zhang Xuxing et al. Genetic Causal Inference Between Inflammatory Proteins and Osteoporosis and the Mediating Effects of Immune Cell Phenotypes:A Mendelian Randomization Study[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(2): 204-213.

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炎症蛋白与骨质疏松症的遗传因果推断及免疫细胞表型的中介效应分析^*

Genetic Causal Inference Between Inflammatory Proteins and Osteoporosis and the Mediating Effects of Immune Cell Phenotypes:A Mendelian Randomization Study

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