Investigating the Role of FES Gene, and Associated DNA Polymorphisms in Relation to Blood Pressure and Coronary Artery Disease

Genome-wide association studies (GWAS) have identified significant associations between SNPs on chromosome 15q26.1 and increased risk for blood pressure (BP) and coronary artery disease (CAD), yet the underlying mechanisms by which these variants influence disease pathogenesis remain unclear.This thesis investigates the role of genetic variation at the FES/FURIN locus in regulating BP and CAD risk, particularly focusing on FES, a non-receptor tyrosine kinase. Chapter 2 presents evidence from genetic analyses, including colocalisation with VSMC eQTLs, which suggest that variants at this locus influence gene expression in BP- and CAD-relevant tissues, contributing to vascular dysfunction.In Chapter 3, the functional role of FES in regulating vascular smooth muscle cell (VSMC) behaviour is explored. Suppression of FES expression led to significant reductions in VSMC migration and proliferation, while enhancing apoptosis, implicating FES in vascular remodelling processes critical to hypertension and CAD. Furthermore, the modulation of FES expression in response to PDGF and TGF-β1 signals its involvement in vascular remodelling, reinforcing its relevance to vascular diseases.Chapter 4 investigates FES in vivo using Fes knockout (KO) mice, revealing elevated systolic and diastolic BP and impaired vascular responses, further confirming the importance of FES in BP regulation. Functional enrichment analysis highlighted immune and metabolic pathway dysregulation underlying these effects. The findings support the hypothesis that FES modulates BP by affecting VSMC contractility and possibly contributing to hypertension and CAD. Despite these insights, the study acknowledges several limitations, including the need for further functional validation of genetic variants in human tissues and more detailed mechanistic studies. The potential risks of targeting FES for hypertension therapy are discussed, considering its involvement in various physiological processes beyond the cardiovascular system, including immune regulation and cancer.This thesis underscores the complex role of FES in vascular biology and highlights its potential as a therapeutic target for hypertension and CAD, while emphasising the need for caution in targeting this protein due to its broader biological functions.