基于双向孟德尔随机化法探讨组织蛋白酶与衰弱的因果关联

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doi:10.6040/j.issn.1671-7554.0.2024.0837

摘要： 目的采用双向两样本孟德尔随机化(two-sample Mendelian randomization, TSMR)方法,从遗传学角度探讨9种组织蛋白酶与衰弱指数之间的因果关系,以期为未来衰弱的预防和治疗策略提供新的见解。方法 9种组织蛋白酶(B、E、F、G、H、L2、O、S和Z)的全基因组关联(genome-wide association study, GWAS)汇总数据来自一项包括3 301名欧洲血统受试者的INTERVAL;衰弱指数的GWAS汇总数据来自一项包括164 610名英国生物银行和10 616名瑞典TwinGene受试者的荟萃分析。以方差逆加权(inverse variance weighted, IVW)作为主要方法,MR-Egger和加权中位数2种回归模型作为补充方法进行TSMR分析。采用MR-Egger截距项和MR-多效性残差和异常值(MR-pleiotropy residual sum and outliers, MR-PRESSO)分析检验水平多效性。应用MR-Egger和IVW方法中的Cochrans Q检验评估异质性。采用留一法进行敏感性分析。采用反向TSMR分析验证结果的稳健性。结果经Bonferroni法校正的正向TSMR分析结果显示,遗传预测的血清组织蛋白酶E水平升高与较高衰弱指数之间存在因果关系(β=0.033,95%CI:0.015~0.050,P<0.001)。反向TSMR分析结果显示,遗传预测的衰弱指数与各种类型的组织蛋白酶之间不存在因果关系(P>0.05/3)。MR-Egger回归模型截距项检验、MR-PRESSO Global检验和Cochrans Q检验的结果显示,筛选出的单核苷酸多态性(single nucleotide polymorphism, SNP)不存在水平多效性和异质性。基于留一法的敏感度分析结果显示,单一SNP不影响因果关联效应值的稳健性。结论在遗传水平上,组织蛋白酶E可作为衰弱易感性的预测性生物标志物,为该疾病的基础和临床研究以及潜在的干预措施提供了新的见解。

关键词: 组织蛋白酶, 衰弱, 孟德尔随机化, 全基因组关联研究

Abstract: Objective To investigate the causal relationship between the nine cathepsins and frailty index at the genetic level using the bidirectional two-sample Mendelian randomization(TSMR), so as to provide new insights for future prevention and treatment strategies for frailty. Methods Genome-wide association study(GWAS)summary data for nine cathepsins(B, E, F, G, H, L2, O, S, and Z)were obtained from the INTERVAL study, which included 3,301 European participants, and GWAS summary data for frailty index were obtained from the meta-analyses including 164,610 UK Biobank and 10,616 Swedish TwinGene participants. TSMR analysis was conducted using inverse variance weighted(IVW)as the primary method, and two regression models, including MR-Egger and weighted median, as the supplementary. In addition, horizontal pleiotropy was tested using the MR-Egger intercept test and MR-pleiotropy residual sum and outliers(MR-PRESSO)analysis, heterogeneity was assessed by applying Cochrans Q test in MR-Egger and IVW methods, and sensitivity analysis was performed using the “leave-one-out” method. Finally, reverse TSMR analysis was used to verify the robustness of the results. Results The forward TSMR analysis corrected by the Bonferroni method revealed a causal relationship between genetically predicted elevated serum cathepsin E level and higher frailty index(β=0.033, 95%CI:0.015-0.050, P<0.001). The reverse TSMR analysis revealed no causal relationship between genetically predicted frailty index and various types of cathepsins(P>0.05/3). The MR-Egger regression model intercept term test, MR-PRESSO Global test and Cochrans Q test showed that the screened single nucleotide polymorphism(SNP)did not have horizontal pleiotropy or heterogeneity. Sensitivity analysis based on the “leave-one-out” method showed that a single SNP did not affect the robustness of the causal association effect values. Conclusion At the genetic level, cathepsin E could potentially serve as a predictive biomarker for susceptibility to frailty, providing new insights for basic and clinical studies of frailty and possible interventions.

Key words: Cathepsins, Frailty, Mendelian randomization, Genome-wide association study

中图分类号:

R195

杨慧,苏士晶,李芬. 基于双向孟德尔随机化法探讨组织蛋白酶与衰弱的因果关联[J]. 山东大学学报 (医学版), 2025, 63(2): 67-76.

YANG Hui, SU Shijing, LI Fen. Study on the causal relationship between cathepsins and risk of frailty based on bidirectional two-sample Mendelian randomization[J]. Journal of Shandong University (Health Sciences), 2025, 63(2): 67-76.

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