B7-H3在脓毒症诊断与预后中的潜在价值:一项孟德尔随机化研究  

Potential value of B7-H3 in sepsis diagnosis and prognosis:A Mendelian randomization study

作　　者：郭名君 何智辉 GUO Mingjun;HE Zhihui(Department of Critical Care Medicine,Third Xiangya Hospital,Central South University,Changsha 410013,China)

机构地区：[1]中南大学湘雅三医院重症医学科,长沙410013

出　　处：《中南大学学报(医学版)》2024年第11期1790-1798,共9页Journal of Central South University :Medical Science

基　　金：国家自然科学基金(82272216)。

摘　　要：目的:脓毒症是全球健康领域的重大挑战,但目前仍缺乏特异性诊断标志物。本研究通过孟德尔随机化(Mendelian randomization,MR)分析方法探讨B7同源物3(B7 homologue 3,B7-H3)与脓毒症的易感性、严重程度及临床结局之间的因果关联,以评估其作为潜在生物标志物的价值。方法:从全基因组关联分析(genome-wideassociation study,GWAS)数据中提取与脓毒症(脓毒症整体、脓毒症28 d内死亡、重症脓毒症及重症脓毒症28 d内死亡)相关的B7-H3单核苷酸多态性(single nucleotide polymorphisms,SNPs)信息,筛选出合适的SNPs作为工具变量。采用逆方差加权法(inverse-variance weighted,IVW)作为主要因果效应估计方法,并使用加权中位数法(weightedmedian,WME)、MR-Egger回归法作为补充方法,对B7-H3与脓毒症及其结局的关联进行MR分析,采用基于约束最大似然和模型平均法(constrained maximum likelihood-model average,cML-MA)进一步增加因果效应估计的可靠性。通过Cochran’s Q检验评估异质性,并采用MR-PRESSO和MR-Egger截距法进行多效性检验。使用留一法进行敏感性分析。以脓毒症为暴露因素,B7-H3为结局,进行反向MR分析,以排除反向因果关联。结果:IVW的分析结果显示:B7-H3与脓毒症的易感性、严重程度及临床结局之间均存在显著的正向因果关联。遗传预测的B7-H3水平每增加1个标准差,发生脓毒症的风险增加10.4%(OR=1.104,95%CI 1.021~1.194,P=0.013),脓毒症28 d内死亡的风险增加26.2%(OR=1.262,95%CI 1.078~1.476,P=0.004),发生重症脓毒症的风险增加22.3%(OR=1.223,95%CI1.023~1.463,P=0.027),发生重症脓毒症且28 d内死亡的风险增加60.2%(OR=1.602,95%CI 1.119~2.294,P=0.010)。IVW、WME、MR-Egger和cML-MA这4种分析方法因果效应方向一致,进一步验证了结果的稳健性和可靠性。Cochran’s Q检验未检测到结果的异质性(P>0.05),MR-PRESSO和MR-Egger截距法均提示结果不存在潜在的水平多效性(均P>0.05)�Objective:Sepsis remains a major global health challenge,yet specific diagnostic biomarkers are still lacking.This study aims to investigate the causal relationship between B7 homologue 3(B7-H3)and sepsis susceptibility,severity,and clinical outcomes using Mendelian randomization(MR)analysis,in order to evaluate its potential as a biomarker.Methods:Genetic data related to sepsis(including overall sepsis,sepsis-related mortality with 28 days,severe sepsis,and severe sepsis with 28-day mortality)were extracted from genome-wide association study(GWAS)datasets.Single nucleotide polymorphisms(SNPs)associated with B7-H3 were selected as instrumental variables.The inverse variance weighted(IVW)was used as the primary approach for causal effect estimation,while weighted median(WME)and MR-Egger regression served as supplementary methods.Additionally,a constrained maximum likelihood-model average(cML-MA)approach was employed to enhance the reliability of causal effect estimation.Cochran’s Q test was conducted to assess heterogeneity,and MR-PRESSO along with the MR-Egger intercept method were used to detect horizontal pleiotropy.Sensitivity analyses were performed using the leave-one-out method.A reverse MR analysis was performed with sepsis as the exposure and B7-H3 as the outcome to exclude potential reverse causation.Results:IVW analysis indicated a significant positive causal association between B7-H3 and sepsis susceptibility,severity,and clinical outcomes.A genetically predicted 1-standard deviation(SD)increase in B7-H3 levels was associated with a 10.4%increased risk of sepsis(OR=1.104,95%CI 1.021 to 1.194,P=0.013),a 26.2%increased risk of sepsis related 28-day mortality(OR=1.262,95%CI 1.078 to 1.476,P=0.004),a 22.3%increased risk of severe sepsis(OR=1.223,95%CI 1.023 to 1.463,P=0.027),and a 60.2%increased risk of severe sepsis with 28-day mortality(OR=1.602,95%CI 1.119 to 2.294,P=0.010).The causal effect direction remained consistent across IVW,WME,MR-Egger,and cML MA analyses,reinforcing the robustness and reliab

关 键 词：B7同源物3 脓毒症 重症脓毒症 孟德尔随机化 生物标志物 易感性 临床结局 

分 类 号：R73[医药卫生—肿瘤]