A Mendelian Randomization Study of Cardiovascular Proteins, Immune Cell Traits, and Lifestyle Factors

We aimed to investigate the causal relationship between cardiovascular-related proteins and osteoporosis and to assess the influence of immune cell traits and lifestyle factors such as smoking and alcohol consumption on osteoporosis risk. A two-sample Mendelian randomization (MR) approach was employed using publicly available genome-wide association study (GWAS) data. Univariable and multivariable MR analyses were conducted using the inverse variance weighted (IVW) method to evaluate causal effects. Additional sensitivity analyses were performed to validate findings. Three cardiovascular proteins showed significant associations with osteoporosis and pathological fractures: TNF-related apoptosis-inducing ligand receptor 2 (OR=0.10), TNF-related activation-induced cytokine (OR=2.90), and C-C motif chemokine 4 (OR=1.12). Lifestyle factors, including household tobacco smoke exposure, daily smoking quantity, and alcohol consumption, were also significantly associated with increased osteoporosis risk. Immune cell traits were identified as potential mediators in the relationship between cardiovascular proteins and osteoporosis. This study highlights a novel link between cardiovascular health and osteoporosis, suggesting that specific proteins increase risk, while immune traits mediate this effect, and lifestyle factors are independent risk factors. These findings underscore the importance of integrated strategies addressing inflammation and lifestyle in osteoporosis prevention and management.