Causal effects of blood pressure and the risk of frailty: a bi-directional two-sample Mendelian randomization study

Observational studies have indicated that high blood pressure (BP) may be a risk factor to frailty. However, the causal association between BP and frailty remains not well determined. The purpose of this bi-directional two-sample Mendelian randomization (MR) study was to investigate the causal relationship between BP and frailty. Independent single nucleotide polymorphisms (SNPs) strongly (P < 5E-08) associated with systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) were selected as instrumental variables. Two different published genome-wide association studies (GWAS) on BP from the CHARGE (n = 810,865) and ICBP (n = 757,601) consortia were included. Summary-level data on frailty index (FI) were obtained from the latest GWAS based on UK Biobank and Swedish TwinGene cohorts (n = 175,226). Inverse variance weighted (IVW) approach with other sensitivity analyses were used to calculate the causal estimate. Using the CHARGE dataset, genetic predisposition to increased SBP (β = 0.135, 95% CI = 0.093 to 0.176, P = 1.73E-10), DBP (β = 0.145, 95% CI = 0.104 to 0.186, P = 3.14E-12), and PP (β = 0.114, 95% CI = 0.070 to 0.157, p = 2.87E-07) contributed to a higher FI, which was validated in the ICBP dataset. There was no significant causal effect of FI on SBP, DBP, and PP. Similar results were obtained from different MR methods, indicating good stability. There was potential heterogeneity detected by Cochran's Q test, but no horizontal pleiotropy was observed in MR-Egger intercept test (P > 0.05). These findings evinced that higher BP and PP were causally associated with an increased risk of frailty, suggesting that controlling hypertension could reduce the risk of frailty.