A common polymorphism that protects from cardiovascular disease increases fibronectin processing and secretion

Recent large scale bioinformatic analyses have identified common genetic variants within the fibronectin (FN1) gene that predispose to cardiovascular disease, through mechanisms that remain to be investigated. This work explores the underlying mechanisms and identifies a novel process controlling fibronectin secretion. First, we demonstrate that higher levels of FN1 protein in plasma associate with a reduced risk of cardiovascular disease.. Next, cellular models were leveraged to demonstrate that the CAD associated region encompasses a L15Q polymorphism within the FN1 signal peptide that impacts secretion of FN1 both qualitatively and quantitatively. Thus, by reducing FN1 secretion, a variant within the signal peptide contributes to lower circulating FN1 and increased CAD risk. In addition to providing novel functional evidence implicating FN1 in cardiovascular disease, these findings demonstrate that a common variant within a secretion signal peptide regulates protein function.