Genetic insights into the risk of frailty on metabolic syndrome and its components: Bidirectional Mendelian...

Previous studies have shown that frailty and metabolic syndrome (Mets) share common pathophysiological mechanisms. However, whether the observed association reflects causality requires clarification. We performed a bidirectional Mendelian randomization study to investigate the causal relationship between frailty, Mets, and their individual components.

Summary-level data from GWAS to identify genetic variants associated with frailty, Mets, and its components among individuals of European ancestry. Inverse variance weighting was utilized as the main method. Using bidirectional Mendelian randomization analysis, we found that the risk of frailty was causally associated with an increased risk of MetS (OR: 2.092, 95%CI: 1.564-2.799) and its components, including waist circumference (OR: 1.349, 95 % CI: 1.181-1.541), hypertension (OR: 1.099, 95 % CI: 1.075-1.125), triglycerides (OR: 1.297, 95 % CI: 1.179-1.428). Conversely, the risk of MetS was causally associated with an increased risk of frailty (OR: 1.048; 95 % CI: 1.024-1.073). however, when removing SNPs assocaited with BMI at the loci significance level and performed MVMR, Mets and frailty were not associated.

These findings suggest a bidirectional causal relationship between frailty and MetS, indicating that genetic factors contributing to frailty also increase the risk of MetS and its components, and vice versa. Furthermore, BMI-related SNPs may act as effect modifiers in the association between MetS and frailty. These insights into the shared pathophysiology of frailty and MetS have implications for the prevention and treatment strategies in elderly individuals with MetS.