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PD-1/PD-L1 and coronary heart disease: a mendelian randomization study
Liangjia Zeng1,2,3, Yinglan Liang3,4, Ruoyun Zhou2,3
1The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Insights
Programmed cell death protein-1 (PD-1) and its ligand PD-L1 show a causal link with chronic ischemic heart disease. This study reveals a bidirectional relationship between PD-1 and chronic ischemic heart disease, and a protective effect of PD-L1.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Genetics
Background:
- Programmed cell death protein-1 (PD-1) and its ligand PD-L1 are implicated in coronary heart disease (CHD) pathogenesis.
- Understanding the causal relationship between PD-1/PD-L1 and specific CHDs is crucial for therapeutic development.
Purpose of the Study:
- To investigate the causal relationship between PD-1/PD-L1 and five specific types of coronary heart disease using Mendelian randomization.
- To validate findings through gene set enrichment analysis (GSEA).
Main Methods:
- Mendelian randomization (MR) analysis utilizing summary-level data from UK Biobank and large genome-wide association studies (GWAS).
- Employed inverse variance-weighted (IVW) meta-analysis, weighted median, MR-Egger, and MR-PRESSO methods.
- Conducted sensitivity analyses including MR-Egger intercept, Cochran's Q test, and leave-one-out analysis.
- Performed GSEA using gene expression data from the GEO database (GSE71226).
Main Results:
- A significant bidirectional causal association was found between PD-1 and chronic ischemic heart disease (CIHD).
- A significant protective association was identified between PD-L1 and CIHD.
- No significant causal relationships were observed between PD-1/PD-L1 and acute myocardial infarction, angina pectoris, coronary atherosclerosis, or unstable angina pectoris.
- GSEA indicated downregulation of the 'PD-L1 expression and PD-1 checkpoint pathway in cancer' in CHD.
Conclusions:
- This study provides genetic evidence for a bidirectional causal link between PD-1 and chronic ischemic heart disease.
- A protective association exists between chronic ischemic heart disease and PD-L1.
- The findings suggest that the PD-1/PD-L1 pathway may be a relevant target for managing chronic ischemic heart disease.
Introduction:
It 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.
Methods:
Publicly 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.
Results:
Gene 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.
Discussion:
This 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.
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