Lymphocyte activation gene 3 and coronary artery disease

Area of Science:

• Immunology
• Cardiovascular Disease Genetics
• Molecular Biology

Background:

• The SCARB1 rs10846744 variant is associated with atherosclerotic disease independently of traditional risk factors.
• A novel connection between rs10846744, lymphocyte activation gene 3 (LAG3), and atherosclerosis was investigated.

Purpose of the Study:

• To investigate the relationship between the SCARB1 rs10846744 variant and LAG3 protein expression and function.
• To determine the association of plasma LAG3 levels with cardiovascular risk factors and coronary heart disease (CHD).

Main Methods:

• In vitro studies using flow cytometry, lipid raft isolation, phosphosignaling, and cytokine measurements.
• Overexpression and silencing of LAG3 protein in cell models.
• Measurement of fasting plasma LAG3 protein in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants.

Main Results:

• rs10846744 risk variant cells showed lower LAG3 protein levels, altered lipid raft localization, and impaired B cell phosphosignaling compared to reference cells.
• Risk cells exhibited higher TNF-α and lower IL-10 secretion.
• Plasma LAG3 levels were lower in HALP carriers of the risk allele and associated with race, age, lipid medications, smoking history, and rs10846744 genotype in MESA.
• Plasma LAG3 was independently associated with HDL-C, IL-10, and predicted CHD risk, especially in individuals with high HDL-C.

Conclusions:

• Plasma LAG3 is a novel independent predictor of HDL-C levels and CHD risk.
• The SCARB1 rs10846744 variant influences immune cell function and LAG3 expression, potentially contributing to atherosclerosis development.