Genetic causal association between heart failure, frailty and poisoning by narcotics and psychodysleptics: A two-sample Mendelian randomization.

Aims: Observational studies have suggested associations between heart failure (HF), frailty and poisoning by narcotics and psychodysleptics (PNP). However, establishing causal relationships has been challenging. This study used a two-sample Mendelian randomization (MR) approach to investigate the genetically proxied causality between HF, frailty and PNP.

Methods: Summary-level data from genome-wide association studies (GWAS) were utilized to investigate the causal relationship between frailty index (FI) and PNP risk, PNP and HF risk, as well as the bidirectional relationship between FI and HF. Various MR methods, including inverse-variance weighted (IVW), MR-Egger, weighted median and weighted mode, were employed. Horizontal pleiotropy, heterogeneities and the robustness of genetic variants were assessed using MR-Egger intercept tests, Cochran's Q test and leave-one-out analyses. The MR-PRESSO outlier test was applied to identify and remove outlier variants to mitigate potential pleiotropy.

Results: Significant genetic causal associations were observed between FI and HF (IVW: OR = 1.42, 95% CI: 1.16-1.74) and between HF and FI (IVW: OR = 1.09, 95% CI: 1.05-1.14). However, no causal relationships were found between other variables. Sensitivity analyses demonstrated no evidence of horizontal pleiotropy or heterogeneity, confirming the robustness of the results.

Conclusions: This MR study provides genetic evidence of a bidirectional causal relationship between FI and HF, highlighting the intertwined nature of frailty and heart failure. No genetically proxied causal associations were observed between FI and PNP or between PNP and HF. Further research, including age-stratified and longitudinal studies, is needed to validate these findings and explore the underlying mechanisms.