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

## TL;DR

Higher blood phytosterol levels may increase frailty risk in older adults, possibly through lipid-related pathways.

## Contribution

This study provides genetic evidence linking blood phytosterols to frailty via mediation by non-HDL-C and ApoB.

## Key findings

- Genetically elevated blood sitosterol is modestly associated with increased Frailty Index risk (OR = 1.035, p = 0.008).
- Non-HDL-C and ApoB mediate about 50% of the effect of blood phytosterols on the Frailty Index.
- No significant association was found between blood phytosterols and Fried Frailty Score.

## Abstract

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.

This Mendelian randomization study found genetically elevated blood sitosterol levels modestly increased Frailty Index risk (OR = 1.035, p = 0.008), with non‐HDL‐C and ApoB mediating ~50% of this effect. No association was observed with Fried Frailty Score, suggesting specificity to cardiometabolic deficits captured by the Frailty Index. Results imply phytosterols may influence frailty through lipid pathways, warranting caution in their therapeutic use for aging populations.