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Higher fibronectin 1 (FN1) protein levels are linked to lower coronary artery disease risk. A common FN1 variant in the signal peptide affects protein secretion and may offer cardioprotection.

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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.