LOX-1 variants modulate the severity of cardiovascular disease: state of the art and future directions.

Atherosclerosis is one of the major causes of cerebral infarction and many other ischemic cardio-cerebrovascular diseases. Although large randomized clinical trials have highlighted the impressive benefits of lipid-lowering therapies, the 50-70% of patients who have achieved their lipid-lowering goal remain at high cardiovascular disease risk. For this reason, there is a need to investigate other markers of atherosclerosis progression. LOX-1 is a scavenger receptor that accepts oxidized low-density lipoproteins as major ligand and internalizes it by endocytosis favoring its retention in subendothelial layer and triggering a wide variety of proatherogenic events. However, other factors such as cytokines, shear stress, and advanced glycation end-products can upregulate LOX-1. LOX-1 is encoded by the OLR1 gene, located in the p12.3-p13 region of chromosome 12. OLR1 gene has different isoforms induced by splicing, or single-nucleotide polymorphisms (SNPs). According to some authors, the expression of these isoforms induces a different effect on atherosclerosis and cardiovascular disease. In particular, LOXIN, an isoform lacking part of the functional domain, exerts an important role in atherosclerosis protection. In other cases, studies on SNPs showed an association with more severe forms, like in the case of 3'UTR polymorphisms. The knowledge of these variants can give rise to the development of new preventive therapies and can lead to the identification of subjects at greater risk of cardiovascular event. In this review, we reported the state of the art regarding SNPs with known effects on OLR1 splicing and how LOX-1 variants modulate the severity of cardiovascular disease.