First evidence for STING SNP R293Q being protective regarding obesity-associated cardiovascular disease in age-advanced subjects - a cohort study.

ABSTRACT

Obesity is a risk factor for several aging-related diseases such as type 2 diabetes, cardiovascular disease, and cancer. Especially, cardiovascular disease is triggered by obesity by inducing vascular senescence and chronic low-grade systemic inflammation, also known as inflamm-aging. Released molecules from damaged cells and their recognition by the innate immune system is one of the mechanisms driving inflamm-aging. Obesity results in mitochondrial damage, leading to endothelial inflammation triggered by cytosolic mtDNA via the cGAS/STING pathway. Recently, we have shown STING SNP R293Q to be associated with a decreased risk for aging-related diseases in current smokers. Since current smoking triggers DNA damage that, similar to obesity, may result in the release of DNA into the cytoplasm, we hypothesized that the cGAS/STING pathway can modify the phenotype of aging also in obese subjects. Therefore, the objective of our study was to investigate whether STING R293Q is associated with aging-related diseases in obese individuals. We indeed show that STING 293Q is associated with protection from combined aging-related diseases (P = 0.014) and, in particular, cardiovascular disease in these subjects (P = 0.010). Therefore, we provide the first evidence that stratification for obesity may reveal new genetic loci determining the risk for aging-related diseases.