PD-1/PD-L1与心肌炎的关系：一项孟德尔随机化研究

Association between PD-1/PD-L1 and Myocarditis: A Mendelian Randomization Study

摘要: 目的：利用两样本，多变量及双向孟德尔随机化(MR)研究设计，探究程序细胞死亡蛋白1 (programmeddeath-1, PD-1)及其配体(PD-1 ligand, PD-L1)与心肌炎风险的因果关联。方法：从公开全基因组关联研究(GWAS)中提取PD-1/PD-L1与心肌炎的工具变量。采用逆方差加权法(IVW)作为主要的MR分析方法，辅以加权中位数(WM)、Robust adjusted profile score (RAPS)、MR-Egger、孟德尔随机化多效性残差和异常值(MR-PRESSO)、Cochran’s Q检验、留一法、水平多效性分析作为敏感性分析。结果：两样本MR的IVW结果提示，PD-L1与心肌炎具有负向因果关联[比值比(OR)，0.619；95%置信区间(CI)，0.434~0.884；P，0.008]，敏感性分析结果表明因果关系稳健。在多变量MR中，PD-L1与心肌炎的负向因果关系依然存在(OR, 0.658; 95% CI, 0.47~0.92, P, 0.015)。PD-1与心肌炎，心肌炎与PD-1/PD-L1的因果关联没有统计学意义。结论：该研究为PD-L1与心肌炎之间的负向因果关联提供了新的证据，而PD-1与心肌炎，心肌炎与PD-1/PD-L1没有直接因果关系。

Abstract: Objective: To investigate the causal association between programmed death-1 (PD-1) and its ligand (PD-1 ligand, PD-L1) and the risk of myocarditis using a two-sample, multivariate and bidirectional Mendelian randomization (MR) study design. Methods: Instrumental variables for PD-1/PD-L1 and myocarditis were extracted from public genome-wide association studies (GWAS). Inverse variance weighting (IVW) was used as the main MR analysis method, supplemented by weighted median (WM), Robusta adjusted profile score (RAPS), MR-Egger, Mendelian randomization pleiotropic residuals and outliers (MR-PRESSO), Cochran’s Q test, leave-one-out method, and horizontal pleiotropy analysis as sensitivity analyses. Results: The IVW results of the two-sample MR suggested that PD-L1 had a negative causal association with myocarditis [odds ratio (OR), 0.619; 95% confidence interval (CI), 0.434~0.884; P, 0.008], and the sensitivity analysis results showed that the causal relationship was robust. In multivariate MR, the negative causal relationship between PD-L1 and myocarditis still existed (OR, 0.658; 95% CI, 0.47-0.92; P, 0.015). The causal association between PD-1 and myocarditis, and between myocarditis and PD-1/PD-L1 was not statistically significant. Conclusion: This study provides new evidence for the negative causal association between PD-L1 and myocarditis, while there is no direct causal relationship between PD-1 and myocarditis, and between myocarditis and PD-1/PD-L1.