Datasheet1_PD-1/PD-L1 and coronary heart disease: a mendelian randomization study.xlsx

IntroductionIt has been found that programmed cell death protein-1 (PD-1) or its ligand PD-L1 may play an important role in the onset and progression of coronary heart disease (CHD). Thus, we conducted this mendelian randomization analysis (MR) to estimate the causal relationship between PD-1/PD-L1 and 5 specific CHDs (chronic ischemic heart disease, acute myocardial infarction, angina pectoris, coronary atherosclerosis, and unstable angina pectoris), complemented by gene set enrichment analysis (GSEA) for further validation.
MethodsPublicly available summary-level data were attained from the UK Biobank with genetic instruments obtained from the largest available, nonoverlapping genome-wide association studies (GWAS). Our analysis involved various approaches including inverse variance-weighted meta-analysis, alternative techniques like weighted median, MR-Egger, MR-multipotency residuals and outliers detection (PRESSO), along with multiple sensitivity assessments such as MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis to evaluate and exclude any anomalies.
ResultsGene expression profile (GSE71226) was obtained from Gene Expression Omnibus (GEO) database for GSEA. IVW analysis showed a causal association between PD-1 and chronic ischemic heart disease (OR, 0.997; 95%CI, 0.995-0.999; P, 0.009), chronic ischemic heart disease and PD-1 (beta, −3.1; 95%CI, −6.017 to −0.183; P, 0.037), chronic ischemic heart disease and PD-L1 (beta, −3.269; 95%CI, −6.197 to −0.341; P, 0.029). No significant causal relationship was found between PD-1/PD-L1 and other 4 CHDs. The accuracy and robustness of these findings were confirmed by sensitivity tests. GSEA found that the KEGG pathway and related core genes of “PD-L1 expression and PD-1 checkpoint pathway in cancer” pathway were downregulated in CHD.
DiscussionThis study provided evidence of a bidirectional causal relationship between PD-1 and chronic ischemic heart disease and a protective association between chronic ischemic heart disease and PD-L1.

研究背景
已有研究证实，程序性细胞死亡蛋白1（programmed cell death protein-1, PD-1）及其配体PD-L1可能在冠心病（coronary heart disease, CHD）的发生与进展中发挥关键作用。为此，本研究开展孟德尔随机化分析（Mendelian randomization analysis, MR），以评估PD-1/PD-L1与5种特定冠心病（慢性缺血性心脏病、急性心肌梗死、心绞痛、冠状动脉粥样硬化及不稳定型心绞痛）之间的因果关联，并辅以基因集富集分析（Gene Set Enrichment Analysis, GSEA）进行进一步验证。

研究方法
本研究从英国生物库（UK Biobank）获取公开的汇总级数据，遗传工具变量则来源于目前已发表的规模最大的非重叠全基因组关联研究（Genome-wide Association Studies, GWAS）。分析采用了多种方法，包括逆方差加权（inverse variance-weighted）Meta分析、加权中位数法（weighted median）、MR Egger回归、MR多效性残差与异常值检测（MR-multipotency residuals and outliers detection, PRESSO），并通过多项敏感性评估——如MR Egger截距检验、科克兰Q检验（Cochran's Q test）及留一法敏感性分析——来评估并排除潜在异常。

研究结果
本研究从基因表达数据库（Gene Expression Omnibus, GEO）获取GSEA所需的基因表达谱数据（GSE71226）。逆方差加权分析显示，PD-1与慢性缺血性心脏病存在因果关联（比值比OR=0.997；95%置信区间CI=0.995~0.999；P=0.009），慢性缺血性心脏病与PD-1（beta值=-3.1；95%CI=-6.017~-0.183；P=0.037）以及慢性缺血性心脏病与PD-L1（beta值=-3.269；95%CI=-6.197~-0.341；P=0.029）均存在显著关联。未发现PD-1/PD-L1与其余4种冠心病存在明确因果关联。敏感性检验证实了上述结果的准确性与稳健性。GSEA分析显示，“癌症中PD-L1表达及PD-1检查点通路”相关的KEGG通路及核心基因在冠心病样本中呈下调表达。

研究讨论
本研究提供了PD-1与慢性缺血性心脏病之间存在双向因果关联的证据，同时提示慢性缺血性心脏病与PD-L1之间存在保护性关联。