Common Polymorphism That Protects From Cardiovascular Disease Increases Fibronectin Processing and Secretion.
Circ Genom Precis Med
; 15(2): e003428, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-35130031
ABSTRACT
BACKGROUND:
Fibronectin (FN1) is an essential regulator of homodynamic processes and tissue remodeling that have been proposed to contribute to atherosclerosis. Moreover, recent large-scale genome-wide association studies (GWAS) have linked common genetic variants within the FN1 gene to coronary artery disease risk.METHODS:
Public databases were analyzed by 2-Sample Mendelian Randomization. Expression constructs encoding short FN1 reporter constructs and full-length plasma FN1 variants were introduced in various cell models. Secreted and cellular levels were then analyzed and quantified by SDS-PAGE and fluorescence microscopy. Mass spectrometry and glycosylation analyses were performed to probe possible posttranscriptional differences.RESULTS:
Bioinformatic analyses revealed that common coronary artery disease risk single nucleotide polymorphisms in the FN1 locus associate with circulating levels of FN1 and that higher FN1 (fibronectin 1) protein levels in plasma are linked to lower coronary artery disease risk. The coronary artery disease-associated FN1 locus encompasses a common polymorphism that translates a L15Q variant situated within the FN1 signal peptide. Introduction of FN1 reporter constructs, differing at position 15, revealed differences in secretion, with the FN1 Q15 variant being less well secreted. Moreover, the L15Q polymorphism was found to alter glycosylation in some cell models but not in human plasma.CONCLUSIONS:
In addition to providing novel functional evidence implicating FN1 in cardioprotection, these findings demonstrate that a common variant within a secretion signal peptide regulates protein function.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença da Artéria Coronariana
/
Doenças Cardiovasculares
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Circ Genom Precis Med
Ano de publicação:
2022
Tipo de documento:
Article