Lymphocyte activation gene 3 and coronary artery disease

Abstract

BACKGROUND:The lipoprotein scavenger receptor BI (SCARB1) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 (LAG3), and atherosclerosis. METHODS:In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein. Fasting plasma LAG3 protein was measured in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants. RESULTS:In comparison with rs10846744 reference (GG homozygous) cells, LAG3 protein levels by flow cytometry (P < 0.001), in lipid rafts stimulated and unstimulated (P = 0.03), and phosphosignaling downstream of B cell receptor engagement of CD79A (P = 0.04), CD19 (P = 0.04), and LYN (P = 0.001) were lower in rs10846744 risk (CC homozygous) cells. Overexpressing LAG3 protein in risk cells and silencing LAG3 in reference cells confirmed its importance in phosphosignaling. Secretion of TNF-α was higher (P = 0.04) and IL-10 was lower (P = 0.04) in risk cells. Plasma LAG3 levels were lower in HALP carriers of the CC allele (P < 0.0001) and by race (P = 0.004). In MESA, race (P = 0.0005), age (P = 0.003), lipid medications (P = 0.03), smoking history (P < 0.0001), and rs10846744 genotype (P = 0.002) were independent predictors of plasma LAG3. In multivariable regression models, plasma LAG3 was significantly associated with HDL-cholesterol (HDL-C) (P = 0.007), plasma IL-10 (P < 0.0001), and provided additional predictive value above the Framingham risk score (P = 0.04). In MESA, when stratified by high HDL-C, plasma LAG3 was associated with coronary heart disease (CHD) (odds ratio 1.45, P = 0.004).CONCLUSION: Plasma LAG3 is a potentially novel independent predictor of HDL-C levels and CHD risk.

Cardiac morbidity in HIV infection is associated with checkpoint inhibitor LAG-3 on CD4 T cells

“…Risk factors for CVD are under intense investigation and involve both traditional and non-traditional factors. A study by Golden et al [ 52 ] found that the lipoprotein scavenger receptor class B type 1 (SCARBI) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. They identified a connection between rs10846744 with sLAG-3 in plasma and concluded that plasma sLAG-3 is an independent predictor of HDL-cholesterol levels and CVD risk.…”

Rediscovering scavenger receptor type BI: surprising new roles for the HDL receptor

“…Finally, in 2016, a large population based study revealed that subjects heterozygous for the P376L mutant form of SR-BI showed significantly increased levels of plasma HDL-cholesterol and had increased risk of cardiovascular disease [11**], now demonstrating that SR-BI in humans was a significant determinant of cardiovascular disease. In further support, the rs10846744 SNP which resides within the enhancer region of SCARBI was recently shown to be significantly associated with atherosclerotic disease [12]. In light of these new findings, some 23 years since SR-BI’s discovery, it appears now that SR-BI has been “re-discovered” as relevant to human disease in a variety of new pathways and mechanisms, as will be covered in this review.…”

“…SR-BI’s role in inflammation has been well studied and now also shown to be relevant in humans [12,13]. Using RNA-sequencing data, lymphocyte activating 3 (LAG3) RNA was identified as a major target driving the effect of SR-BI on inflammation, since its expression was significantly lower in homozygous carriers of the SR-BI rs10846744 risk allele [12].…”

“…Using RNA-sequencing data, lymphocyte activating 3 (LAG3) RNA was identified as a major target driving the effect of SR-BI on inflammation, since its expression was significantly lower in homozygous carriers of the SR-BI rs10846744 risk allele [12]. LAG3 competes with CD4 in T cells by binding higher affinity MHC class II to negatively regulate T cell activation.…”

Heart failure in cancer: role of checkpoint inhibitors

“…Cells presenting the noncoding variant produced less amounts of LAG-3 under basal conditions and following BCR engagement. Plasma LAG-3 levels were found lower in hyperalphalipoproteinemia patients and significantly associate with HDL and IL-10 concentration in plasma (74). Therefore, LAG-3 may confer protective immune response in the heart, although this hypothesis was not formally addressed.…”