Genetic Evidence on the Role of Blood Phytosterols in Frailty: A Mendelian Randomization Study

Phytosterols have been recommended as a lifestyle intervention for early lipid management-which has a significant impact on frailty. However, their effect on frailty remains unclear. Studies have shown that genetic proxied total blood phytosterol affects the development of cardiovascular disease through non-HDL-c and apolipoprotein B mediation, which makes phytosterol an underlying risk factor for frailty. The aim of this Mendelian randomization (MR) study was to investigate the genetic associations between phytosterols and frailty. We used univariate Mendelian randomization (UVMR) to assess the causal effects of blood phytosterols on the Frailty Index (FI) and Fried Frailty Score (FFS). We also employed multivariate Mendelian randomization (MVMR) and Two-step MR (TSMR) to evaluate the mediating role of blood lipids in the relationship between blood phytosterols and FI. We used the product of coefficients method to calculate the mediating effect. The inverse-variance weighted method was used as the primary analysis. Genetically proxied higher levels of blood total sitosterol were significantly associated with a higher risk of Frailty Index (OR = 1.035, 95% CI = 1.009-1.061, p = 0.008). MVMR analysis revealed that the causal association between blood total sitosterol and Frailty Index was attenuated after adjusting for non-HDL-C and APOB. Non-HDL-C and APOB mediated 54.3% (21.1%, 87.5%) and 49.9% (17.7%, 82.1%) of the effect of blood phytosterols on the Frailty Index, respectively. No significant association between blood phytosterols and Fried Frailty Score was detected. This study suggests a modest association between blood phytosterols and an increased risk of FI. Furthermore, non-HDL-C and APOB may mediate a significant proportion of the association between blood sitosterol and FI. The differential effects of blood phytosterols on FI and FFS outcomes may indicate a mediating role of specific health deficits, particularly cardiometabolic factors.