Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sam...Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.展开更多
Mendelian randomization(MR)is widely used in causal mediation analysis to control unmeasured confounding effects,which is valid under some strong assumptions.It is thus of great interest to assess the impact of violat...Mendelian randomization(MR)is widely used in causal mediation analysis to control unmeasured confounding effects,which is valid under some strong assumptions.It is thus of great interest to assess the impact of violations of these MR assumptions through sensitivity analysis.Sensitivity analyses have been conducted for simple MR-based causal average effect analyses,but they are not available for MR-based mediation analysis studies,and we aim to fill this gap in this paper.We propose to use two sensitivity parameters to quantify the effect due to the deviation of the IV assumptions.With these two sensitivity parameters,we derive consistent indirect causal effect estimators and establish their asymptotic propersties.Our theoretical results can be used in MR-based mediation analysis to study the impact of violations of MR as-sumptions.The finite sample performance of the proposed method is illustrated through simulation studies,sensitivity ana-lysis,and application to a real genome-wide association study.展开更多
目的评估炎症因子与骨质疏松症(osteoporosis,OP)之间的因果关系。方法从GWAScatalog数据库中获取41个炎症因子和骨密度(bone mineral density,BMD)的GWAS数据,芬兰数据库中获取OP的GWAS数据。采用逆方差加权法(IVW)、MR-Egger回归法(M...目的评估炎症因子与骨质疏松症(osteoporosis,OP)之间的因果关系。方法从GWAScatalog数据库中获取41个炎症因子和骨密度(bone mineral density,BMD)的GWAS数据,芬兰数据库中获取OP的GWAS数据。采用逆方差加权法(IVW)、MR-Egger回归法(MER)、加权中位数法(WME)、简单中位数法和加权中值方法进行两样本孟德尔随机化分析,并以IVW法为主要分析方法。再进行敏感性分析以检验结果的可靠性,留一法评估单核苷酸多态性对结果的影响。最后进行药物预测和分子对接进一步验证炎症因子的药理价值。结果研究表明炎症因子与OP和BMD之间存在因果关系。其中肿瘤坏死因子相关的凋亡诱导配体(TRAIL)和单核细胞趋化蛋白1(MCP-1/MCAF)与OP发生风险呈正相关;肿瘤坏死因子β(TNF-β)与0~15岁人群的BMD呈负相关;白细胞介素7(IL-7)与15~30岁人群的BMD呈负相关;肝细胞生长因子(HGF)与30~45岁人群的BMD呈负相关;巨噬细胞炎性蛋白1α(MIP-1α)和巨噬细胞集落刺激因子(M-CSF)与60岁以上人群的BMD呈负相关;MIP-1α与全年龄段人群的BMD呈负相关。此外,分子对接证明了药物与蛋白质的良好结合,进一步证实了这些靶点的药理价值。结论通过孟德尔随机化方法全面评估了41种炎症因子对OP和BMD的因果效应,表明炎症因子与OP和BMD之间存在因果关联,提示OP患者可以在疾病早期通过干预炎症因子进而干预OP的发生发展过程。展开更多
目的通过孟德尔随机化(Mendelian randomization,MR)分析探究免疫细胞与慢性胰腺炎(chronic pancreatitis,CP)之间的因果关系。方法本研究的免疫细胞表型和CP的全基因组关联研究(genome-wide association studies,GWAS)数据来自公开数据...目的通过孟德尔随机化(Mendelian randomization,MR)分析探究免疫细胞与慢性胰腺炎(chronic pancreatitis,CP)之间的因果关系。方法本研究的免疫细胞表型和CP的全基因组关联研究(genome-wide association studies,GWAS)数据来自公开数据库,共纳入731种免疫细胞表型。采用双样本双向MR分析法探索免疫细胞与CP之间的因果关系,并使用多种敏感性分析方法对结果的异质性和水平多效性进行验证。结果共发现33个免疫细胞表型与CP存在因果关联,其中18个表现为抑制因素,调节性T细胞(Treg)细胞群中的CD25 on CD4^(+)表现出最显著的抑制作用;其余15个则表现为风险因素,成熟T细胞组的CD8 on TD CD8br、TBNK组的CD8br AC以及Treg组的CD39^(+)CD8br%T cell和CD28 on CD4^(+)表现出显著的促进作用。反向MR结果也进一步证明了因果关系的单向性。结论通过MR方法揭示了免疫细胞与CP之间的密切联系,凸显了免疫系统与CP之间复杂的相互作用模式。展开更多
目的 使用孟德尔随机化(MR)分析方法探究近视与特定免疫细胞之间的因果关系。方法 对OPEN-GWAS数据库进行数据挖掘和分析,选取731种免疫细胞特征作为暴露因素,近视作为结局因素。设置显著阈值,筛选与免疫细胞及近视显著相关的单核苷酸...目的 使用孟德尔随机化(MR)分析方法探究近视与特定免疫细胞之间的因果关系。方法 对OPEN-GWAS数据库进行数据挖掘和分析,选取731种免疫细胞特征作为暴露因素,近视作为结局因素。设置显著阈值,筛选与免疫细胞及近视显著相关的单核苷酸多态性(SNP),并排除弱工具变量偏倚的影响。主要的分析方法是采用逆方差加权法(IVW),同时使用简单模式法、加权中位数法、加权模式法和MR-Egger回归进行数据分析。通过比值比和95%置信区间评估循环免疫细胞与近视的因果关系。对于符合假设的免疫细胞SNP,采用Cochran Q检验来评估异质性,并使用MR-Egger回归和MR-PRESSO法来排除SNP的水平多效性,利用留一法分析来评估显著结果是否由单个SNP影响。为了避免反向因果关系,本研究将近视作为暴露变量,免疫细胞表型为结果变量进行反向MR分析。此外,采用多变量MR分析(MVMR)评估这些免疫细胞对近视的因果和独立效应。结果 (1)两样本MR IVW法结果显示,Memory B cell AC(B细胞)和CD24+CD27+AC(B细胞)是近视发生的保护因素。Naive CD8br%CD8br(T细胞)、CD39+CD8br AC(T细胞)、CD25 on CD39+activated Treg(T细胞)、PDL-1 on CD14+CD16+monocyte(单核细胞)以及CD80 on myeloid DC(髓系树突状细胞)是近视发生的风险因素,且其余MR-Egger等方法结果与IVW方向一致。MR-Egger回归和MR-PRESSO分析表明,不存在水平多效性(P>0.05)。(2)双样本反向MR分析结果显示,近视与上述7种免疫细胞之间均无双向因果关系(均为P>0.05)。(3)在MVMR分析中,CD80 on myeloid DC与近视之间的显著因果关系在调整了潜在的混杂变量后依然稳健。结论 本研究通过遗传学手段,揭示了多种免疫表型与近视之间的复杂因果关系,展示了免疫系统与近视之间相互作用的复杂调控模式。展开更多
基金This work was supported by the National Natural Science Foundation (82273506,82273508)the Hunan Provincial Health Commission Scientific Research Plan Project (D202304128334),China。
文摘Objective:The causal relationship between eczema and autoimmune diseases has not been previously reported.This study aims to evaluate the causal relationship between eczema and autoimmune diseases.Methods:The two‐sample Mendelian randomization(MR)method was used to assess the causal effect of eczema on autoimmune diseases.Summary data from the Genome-Wide Association Study Catalog(GWAS)were obtained from the Integrative Epidemiology Unit(IEU)database.For eczema and autoimmune diseases,genetic instrument variants(GIVs)were identified according to the significant difference(P<5×10−8).Causal effect estimates were generated using the inverse‐variance weighted(IVW)method.MR Egger,maximum likelihood,MR-PRESSO,and MR-RAPS methods were used for alternative analyses.Sensitivity tests,including heterogeneity,horizontal pleiotropy,and leave-one-out analyses,were performed.Finally,reverse causality was assessed.Results:Genetic susceptibility to eczema was associated with an increased risk of Crohn’s disease(OR=1.444,95%CI 1.199 to 1.738,P<0.001)and ulcerative colitis(OR=1.002,95%CI 1.001 to 1.003,P=0.002).However,no causal relationship was found for the other 6 autoimmune diseases,including systemic lupus erythematosus(SLE)(OR=0.932,P=0.401),bullous pemphigoid(BP)(OR=1.191,P=0.642),vitiligo(OR=1.000,P=0.327),multiple sclerosis(MS)(OR=1.000,P=0.965),ankylosing spondylitis(AS)(OR=1.001,P=0.121),rheumatoid arthritis(RA)(OR=1.000,P=0.460).Additionally,no reverse causal relationship was found between autoimmune diseases and eczema.Conclusion:Eczema is associated with an increased risk of Crohn’s disease and ulcerative colitis.No causal relationship is found between eczema and SLE,MS,AS,RA,BP,or vitiligo.
基金This work was supported by the National Natural Science Foundation of China(12171451,72091212).
文摘Mendelian randomization(MR)is widely used in causal mediation analysis to control unmeasured confounding effects,which is valid under some strong assumptions.It is thus of great interest to assess the impact of violations of these MR assumptions through sensitivity analysis.Sensitivity analyses have been conducted for simple MR-based causal average effect analyses,but they are not available for MR-based mediation analysis studies,and we aim to fill this gap in this paper.We propose to use two sensitivity parameters to quantify the effect due to the deviation of the IV assumptions.With these two sensitivity parameters,we derive consistent indirect causal effect estimators and establish their asymptotic propersties.Our theoretical results can be used in MR-based mediation analysis to study the impact of violations of MR as-sumptions.The finite sample performance of the proposed method is illustrated through simulation studies,sensitivity ana-lysis,and application to a real genome-wide association study.
文摘目的评估炎症因子与骨质疏松症(osteoporosis,OP)之间的因果关系。方法从GWAScatalog数据库中获取41个炎症因子和骨密度(bone mineral density,BMD)的GWAS数据,芬兰数据库中获取OP的GWAS数据。采用逆方差加权法(IVW)、MR-Egger回归法(MER)、加权中位数法(WME)、简单中位数法和加权中值方法进行两样本孟德尔随机化分析,并以IVW法为主要分析方法。再进行敏感性分析以检验结果的可靠性,留一法评估单核苷酸多态性对结果的影响。最后进行药物预测和分子对接进一步验证炎症因子的药理价值。结果研究表明炎症因子与OP和BMD之间存在因果关系。其中肿瘤坏死因子相关的凋亡诱导配体(TRAIL)和单核细胞趋化蛋白1(MCP-1/MCAF)与OP发生风险呈正相关;肿瘤坏死因子β(TNF-β)与0~15岁人群的BMD呈负相关;白细胞介素7(IL-7)与15~30岁人群的BMD呈负相关;肝细胞生长因子(HGF)与30~45岁人群的BMD呈负相关;巨噬细胞炎性蛋白1α(MIP-1α)和巨噬细胞集落刺激因子(M-CSF)与60岁以上人群的BMD呈负相关;MIP-1α与全年龄段人群的BMD呈负相关。此外,分子对接证明了药物与蛋白质的良好结合,进一步证实了这些靶点的药理价值。结论通过孟德尔随机化方法全面评估了41种炎症因子对OP和BMD的因果效应,表明炎症因子与OP和BMD之间存在因果关联,提示OP患者可以在疾病早期通过干预炎症因子进而干预OP的发生发展过程。
文摘目的通过孟德尔随机化(Mendelian randomization,MR)分析探究免疫细胞与慢性胰腺炎(chronic pancreatitis,CP)之间的因果关系。方法本研究的免疫细胞表型和CP的全基因组关联研究(genome-wide association studies,GWAS)数据来自公开数据库,共纳入731种免疫细胞表型。采用双样本双向MR分析法探索免疫细胞与CP之间的因果关系,并使用多种敏感性分析方法对结果的异质性和水平多效性进行验证。结果共发现33个免疫细胞表型与CP存在因果关联,其中18个表现为抑制因素,调节性T细胞(Treg)细胞群中的CD25 on CD4^(+)表现出最显著的抑制作用;其余15个则表现为风险因素,成熟T细胞组的CD8 on TD CD8br、TBNK组的CD8br AC以及Treg组的CD39^(+)CD8br%T cell和CD28 on CD4^(+)表现出显著的促进作用。反向MR结果也进一步证明了因果关系的单向性。结论通过MR方法揭示了免疫细胞与CP之间的密切联系,凸显了免疫系统与CP之间复杂的相互作用模式。
文摘目的 使用孟德尔随机化(MR)分析方法探究近视与特定免疫细胞之间的因果关系。方法 对OPEN-GWAS数据库进行数据挖掘和分析,选取731种免疫细胞特征作为暴露因素,近视作为结局因素。设置显著阈值,筛选与免疫细胞及近视显著相关的单核苷酸多态性(SNP),并排除弱工具变量偏倚的影响。主要的分析方法是采用逆方差加权法(IVW),同时使用简单模式法、加权中位数法、加权模式法和MR-Egger回归进行数据分析。通过比值比和95%置信区间评估循环免疫细胞与近视的因果关系。对于符合假设的免疫细胞SNP,采用Cochran Q检验来评估异质性,并使用MR-Egger回归和MR-PRESSO法来排除SNP的水平多效性,利用留一法分析来评估显著结果是否由单个SNP影响。为了避免反向因果关系,本研究将近视作为暴露变量,免疫细胞表型为结果变量进行反向MR分析。此外,采用多变量MR分析(MVMR)评估这些免疫细胞对近视的因果和独立效应。结果 (1)两样本MR IVW法结果显示,Memory B cell AC(B细胞)和CD24+CD27+AC(B细胞)是近视发生的保护因素。Naive CD8br%CD8br(T细胞)、CD39+CD8br AC(T细胞)、CD25 on CD39+activated Treg(T细胞)、PDL-1 on CD14+CD16+monocyte(单核细胞)以及CD80 on myeloid DC(髓系树突状细胞)是近视发生的风险因素,且其余MR-Egger等方法结果与IVW方向一致。MR-Egger回归和MR-PRESSO分析表明,不存在水平多效性(P>0.05)。(2)双样本反向MR分析结果显示,近视与上述7种免疫细胞之间均无双向因果关系(均为P>0.05)。(3)在MVMR分析中,CD80 on myeloid DC与近视之间的显著因果关系在调整了潜在的混杂变量后依然稳健。结论 本研究通过遗传学手段,揭示了多种免疫表型与近视之间的复杂因果关系,展示了免疫系统与近视之间相互作用的复杂调控模式。
