A Mendelian Randomization Study on the Causal Associations Between Six Blood Pressure-related Hormones and Frailty

Observational studies suggest a link between hypertension, blood pressure- related hormones, and frailty. However, the causal nature of the association between these hormones and frailty remains unclear. This study employs Mendelian randomization (MR) to investigate the causal relationships between frailty and genetically influenced blood pressure-related hormones.

Genetic variants were selected as instrumental variables (IVs) from genome-wide association studies (GWAS) using strict significance thresholds. To evaluate causal relationships, a twosample MR analysis was performed. The primary method for estimating causal effects was the inverse variance weighted (IVW) approach, supplemented by the weighted median, weighted mode, and MR-Egger methods. Sensitivity analyses, including Cochran's Q tests, MR-Egger, MR-PRESSO, and leave-one-out assessments, were conducted to identify potential heterogeneity and pleiotropy.

No causal associations between frailty index and genetically determined levels of well- recognized hormones regulating blood pressure, such as ACE (IVW: OR: 0.9934, 95%CI: 0.9847-1.0022, P=0.1425) and ACE2 (IVW: OR: 1.004, 95%CI: 0.9858-1.0226, P=0.6679), were found.

The absence of a detectable causal effect suggests that previously observed associations in observational studies may be influenced by confounding factors. These findings challenge the hypothesis that these hormones are primary drivers of frailty from a genetic standpoint, highlighting the complexity of frailty's etiology, which may be more strongly influenced by non-genetic or environmental factors. Study limitations include the potential for weak instrument bias in smaller GWAS datasets.

Our findings do not support a causal relationship between genetically determined levels of six major blood pressure-related hormones and the frailty index in European populations.