Linking SIRT1 Variants to Metabolic and Cardiovascular Phenotypes: Insights from Population Genetics and In Silico Structural Analysis.

The sirtuin (SIRT) family, particularly SIRT1, plays a pivotal role in cell metabolism, inflammation, and aging through its NAD+-dependent deacetylase activity. SIRT1 modulates signaling pathways by targeting numerous regulatory proteins and transcription factors (TFs). Among these is the forkhead TF FOXO1, which plays a key role in regulating genes associated with inflammation (TNF-α), oxidative stress, and glucose and lipid metabolism (G6Pase and PPARG). SIRT1 additionally regulates other important TFs involved in inflammation and cancer, such as HIF-1α, HIF-2α, and p53, all of which are directly associated with lifespan. Here we describe the association between SIRT1 gene variants and various pathologic conditions in different population groups (African, European, and Asian). We discuss the association of SIRT1 polymorphisms with cardiovascular health, lifespan, and diseases, including metabolic disorders, obesity, hypertension, and systemic lupus erythematosus, emphasizing their relevance for personalized medicine. Our findings highlight the dual role of SIRT1 in metabolic regulation, where its overexpression can both protect against insulin resistance and disrupt lipid homeostasis. Additionally, using the variant rs587776957 as an example, we evaluated its effect on the secondary structure of the protein. Our in silico analysis assessed the effect of the polymorphism on the protein’s structural stability, confirming its potential to destabilize the secondary structure of SIRT1. The primary goal of this study was a comprehensive assessment of the clinical significance of SIRT1 gene genetic variants across different populations, with a particular focus on their role in regulating metabolism, lifespan, and cardiovascular health. To achieve this, we combined a review and bioinformatic analysis of population-specific associations with an in-depth in silico investigation analyzing the structural impact of the rs587776957 variant on the SIRT1 protein.