Common Polymorphism That Protects From Cardiovascular Disease Increases Fibronectin Processing and Secretion.

Area of Science:

• Genetics
• Cardiovascular Biology
• Protein Biochemistry

Background:

• Fibronectin 1 (FN1) regulates hemodynamics and tissue remodeling, potentially contributing to atherosclerosis.
• Genome-wide association studies link genetic variants in FN1 to coronary artery disease (CAD) risk.

Purpose of the Study:

• To investigate the association between FN1 genetic variants, circulating FN1 levels, and CAD risk.
• To explore the functional impact of a specific FN1 variant on protein secretion and posttranslational modification.

Main Methods:

• Two-sample Mendelian randomization analysis of public databases.
• Expression of FN1 reporter constructs and full-length variants in cell models.
• Quantification of secreted and cellular FN1 levels using SDS-PAGE and fluorescence microscopy.
• Mass spectrometry and glycosylation analyses to assess posttranscriptional differences.

Main Results:

• Common CAD risk single nucleotide polymorphisms in the FN1 locus associate with circulating FN1 levels.
• Higher plasma FN1 protein levels correlate with lower CAD risk.
• A common L15Q polymorphism in the FN1 signal peptide reduces protein secretion and alters glycosylation in some cell models.

Conclusions:

• FN1 plays a role in cardioprotection.
• A common variant within the FN1 signal peptide regulates protein function and secretion.