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Soluble Immune Checkpoint Protein and Lipid Network Associations with All-Cause Mortality Risk: Trans-Omics for

Annabelle Rodriguez, Chaojie Yang, Wenqi Gan

Medrxiv : the Preprint Server for Health Sciences

|January 20, 2025

Summary

Immune checkpoint therapies may increase cardiovascular risks. Specific plasma proteins, LAG3 and HAVCR2, are linked to mortality, and genetic variants associated with HDL cholesterol may offer further risk prediction.

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Area of Science:

Cardiovascular disease
Oncology
Genetics
Proteomics

Background:

Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment.
Adverse cardiovascular events are an emerging concern with ICI use.
Understanding the molecular mechanisms linking ICIs to cardiovascular risk is crucial.

Purpose of the Study:

To investigate the association between immune checkpoint plasma proteins and cardiovascular risk factors.
To explore the protein network associated with high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
To assess the association of these protein networks with all-cause mortality risk.

Main Methods:

Utilized datasets from the Trans-Omics for Precision Medicine program, including the Multi-Ethnic Study of Atherosclerosis, Jackson Heart Study (JHS), and Framingham Heart Study.
Examined associations between immune checkpoint plasma proteins, HDL-C, and LDL-C.
Performed colocalization analysis using genome-wide association studies (GWAS) of HDL-C/LDL-C and protein quantitative trait loci (pQTLs) from JHS and Atherosclerosis Risk in Communities.

Main Results:

Plasma levels of Lymphocyte-Activation Gene 3 (LAG3) and Hepatitis A Virus Cellular Receptor 2 (HAVCR2) were significantly associated with mortality risk.
TFF3 rs60467699 and CD36 rs3211938 variants significantly colocalized with HDL-C.
No significant colocalization was observed between genetic variants and LDL-C.

Conclusions:

Plasma LAG3 and HAVCR2 levels are associated with increased mortality risk.
Specific genetic variants linked to HDL-C may contribute to cardiovascular risk.
Measuring plasma LAG3, HAVCR2, and associated proteins, along with targeted genotyping, could help identify high-risk patients.