目的:探讨免疫细胞特征与骨质疏松症(osteoporosis，OP)的因果关系。方法:分别从IEU OpenGWAS project数据库和FINNGEN数据库中筛选并获得731个免疫细胞特征的全基因组关联研究(genome-wide association study，GW AS)数据集和OP的GW AS数据集。基于工具变量筛选标准，筛选符合要求的免疫细胞特征的单核苷酸多态性(single nucleotide polymorphism，SNP)位点和OP的SNP位点。将筛选的免疫细胞特征的SNP位点作为工具变量，采用逆方差加权法(inverse variance weighted，IVW)、MR-Egger、加权中位数、简单模式和加权模式等进行正向孟德尔随机化(Mendelian randomization，MR)分析，评估免疫细胞特征与OP的因果关系。采用MR-presso检验进行水平多效性检验，采用Cochran's Q检验评估IVW法和MR Egger法分析结果的异质性，采用留一法评估MR分析结果的稳定性。将筛选的OP的SNP位点作为工具变量，以正向MR分析获得的与OP具有可靠因果关系的免疫细胞特征为结局进行反向MR分析。结果:32个免疫细胞特征与OP存在可靠的因果关系，其中包含7个绝对细胞计数(absolute cell counts，AC)特征、13 个中位荧光强度(median fluorescence intensity，MFI)特征、12 个相对细胞计数(relative cell counts，RC)特征。在 7 个 AC 特征中，Sw mem AC、IgD-CD38dim AC、HLA DR+NK AC 与 OP 呈负向因果关系，CD62L-myeloid DC AC、CD33br HLA DR+AC、DN(CD4-CD8-)AC、CD25++CD8br AC 与 OP 呈正向因果关系;在 13 个 MFI 特征中，BAFF-Ron IgD-CD38br、CD3 on CD8br、CD3 on CD39+CD4+、CD16-CD56 on NK、CD28 on CD4 Treg、CD16 on CD14-CD16+monocyte、CD8 on TD CD8br 与 OP 呈负向因果关系，CD19 on IgD-CD38br、CD86 on myeloid DC、HLA DR on CD14+CD16-monocyte、HLA DR on CD14+monocyte、CD45 on CD33br HLA DR+CD14-、HLA DR on CD33br HLA DR+CD14dim 与 OP 呈正向因果关系;在 12 个 RC 特征中，IgD+CD38dim％lymphocyte、CD11c+CD62L-monocyte％monocyte、TD CD8br％CD8br、CD39+CD8br％T cell 与 OP 呈负向因果关系，IgD-CD38dim％B cell、CD62L-DC％DC、CD8br％leukocyte、CD8br and CD8dim％leukocyte、NKT％T cell、NKT％lymphocyte、HLA DR+CD8br％lymphocyte、CD3-lymphocyte％leukocyte与OP呈正向因果关系。结论:部分免疫细胞特征与OP之间存在因果关系，这为探究免疫系统与OP间的作用机制提供了线索和方向。
The causal relationship between immune cell signatures and osteoporosis:a bidirectional mendelian randomiza-tion study
Objective:To explore the causal relationship between immune cell signatures and osteoporosis(OP).Methods:The ge-nome-wide association study(GWAS)datasets about 731 immune cell signatures and OP were retrieved and extracted from the IEU OpenG-WAS project database and FINNGEN database,respectively.According to the instrumental variable screening criteria,the eligible single nu-cleotide polymorphism(SNP)loci for immune cell signatures and OP were screened as the instrumental variables,and then a forward mende-lian randomization(MR)analysis was conducted by using inverse variance weighted(IVW),MR-Egger regression,weighted median estima-tor,simple mode,and weighted mode to assess the causal relationship between immune cell signatures and OP.In addition,the horizontal pleiotropy was examined by MR-presso test,the heterogeneity of the results analyzed by IVW method and MR-egger regression was assessed by Cochran's Q test,and the stability of the MR analysis results was evaluated by leave-one-out(LOO)test.Furthermore,a reverse MR analysis was conducted by taking the screened OP SNP loci as instrumental variable,and the immune cell signatures having a reliable causal relationship to OP obtained from the forward MR analysis as the outcome variable.Results:Seven absolute cell counts(AC)signa-tures,13 median fluorescence intensity(MFI)signatures and 12 relative cell counts(RC)signatures exhibited a reliable causal relationship with OP.Among the 7 AC signatures,the Sw mem AC,IgD-CD38dim AC,and HLA DR+NK AC showed a inverse causal relationship with OP,while the CD62L-myeloid DC AC,CD33br HLA DR+AC,DN(CD4-CD8-)AC,and CD25++CD8br AC presented a positive causal relationship with OP.Among the 13 MFI signatures,the BAFF-R on IgD-CD38br,CD3 on CD8br,CD3 on CD39+CD4+,CD16CD56 on NK,CD28 on CD4 Treg,CD16 on CD14-CD16+monocyte,and CD8 on TD CD8br showed a inverse causal relationship with OP,while the CD19 on IgD-CD38br,CD86 on myeloid DC,HLA DR on CD14+CD16-monocyte,HLA DR on CD14+monocyte,CD45 on CD33br HLA DR+CD14-,HLA DR on CD33br HLA DR+CD14dim presented a positive causal relationship with OP.Among the 12 RC signatures,the IgD+CD38dim％lymphocyte,CD11c+CD62L-monocyte％monocyte,TD CD8br％CD8br,and CD39+CD8br％T cell showed a inverse causal relationship with OP,while the IgD-CD38dim％B cell,CD62L-DC％DC,CD8br％leukocyte,CD8br and CD8dim％leukocyte,NKT％T cell,NKT％lymphocyte,HLA DR+CD8br％lymphocyte,and CD3-lymphocyte％leukocyte presented a positive causal relation-ship with OP.Conclusion:A causality exists between partial immune cell signatures and OP,which provides the clues and directions for ex-ploring the mechanism of action between the immune system and OP.
osteoporosisimmune cell characteristicsMendelian randomization analysisgenome-wide association study
万方数据
维普
