Frailty index and risk of cardiovascular diseases: a mendelian randomization study

Background: Previous epidemiological evidence has suggested that frailty status might be associated with cardiovascular diseases (CVDs). However, the exact causality remains unestablished. In this study, we employed Mendelian randomization and sought to investigate the potential causality in association of frailty index (FI) with cardiovascular outcomes [coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF)]. Methods: Independent single nucleotide polymorphisms (SNPs) at genome-wide significance for FI were obtained from a recent genome-wide association study (GWAS) meta-analysis of European descent (n=175,226). The association of these SNPs with CVDs was examined in summary statistics from corresponding GWASs of European descent (CAD: 184,305 cases and 60,801 controls; MI: 184,305 cases and 43,676 controls; AF: 1,030,836 cases and 60,620 controls; and HF: 977,323 cases and 47,309 controls). Replication analyses were performed using GWAS datasets from FinnGen. Results: In the meta-analysis of inverse-variance weighted estimates from different data sources, genetically determined higher FI conferred an odds ratio (OR) of 1.46 [95% confidence interval (CI): 1.13 to 1.87; P=0.003] for CAD, 1.62 (95% CI: 1.21 to 2.17, P=0.001) for MI, and 1.46 (95% CI: 1.24 to 1.72; P=4.89x10(-6)) for HF. However, FI failed to be potentially influential on AF risk (OR, 1.43; 95% CI: 0.93 to 1.66; P=0.107). Several complementary analyses also received broadly concordant results. Conclusions: We have provided genetic evidence of a causal association between FI and the risk of CAD, MI, and HF. Further studies are warranted to clarify whether FI is causally related to AF risk.