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Causal associations of fatigue and functional outcome after ischemic stroke: a mediation Mendelian randomization
Ping Jiang1, Ying Gao1,2, Leyi Zhang1
1Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
Background And Objectives:
Fatigue has been associated with adverse effects on recovery from ischemic stroke based on previous observational research. The purpose of our study was to explore the potential causal association of fatigue with poor functional outcome after ischemic stroke by employing Mendelian randomization (MR).
Methods:
A set of instrumental variables, comprising 36 single-nucleotide polymorphisms (SNPs) that are only related to fatigue, were derived from a genome-wide association study (GWAS) that included 449,019 general individuals. The functional outcomes after ischemic stroke were derived from a GWAS (Genetics of Ischemic Stroke Functional Outcome Network) involving 6,021 survivors. Two-sample MR methods were used to assess the causal effect, including inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode. In bidirectional MR analysis, the reverse causal association was analyzed using the Wald ratio method. The mediation effects of lipid metabolites were analyzed using two-step MR analysis.
Results:
Genetic liability to fatigue was causally associated with the poor functional outcome (modified Rankin Scale ≥3 at 3 months) after ischemic stroke (OR = 4.20, 95%CI [1.11-15.99], p < 0.05). However, genetic predicted poor functional outcome after ischemic stroke was not associated with fatigue (OR = 1.00, 95%CI [0.99-1.02], p > 0.05). The results of the two-step MR showed that cholesteryl esters to total lipids ratio in large very low-density lipoprotein (VLDL) (ME = -0.13, p < 0.05); concentration of very large VLDL particles (ME = -0.13, p < 0.05); free cholesterol in large VLDL (ME = -0.13, p < 0.05); free cholesterol to total lipids ratio in very large VLDL (ME = -0.22, p < 0.05); phospholipids in large VLDL (ME = -0.15, p < 0.05); phospholipids in very large VLDL (ME = -0.13, p < 0.05); phospholipids to total lipids ratio in large high-density lipoprotein (HDL) (ME = -0.17, p < 0.05); total lipids in very large VLDL (ME = -0.14, p < 0.05); triglycerides in small VLDL (ME = -0.11, p < 0.05); and triglycerides to total lipids ratio in large HDL (ME = -0.10, p < 0.05) assumed a pivotal role in mediating the association between fatigue and poor functional outcome after ischemic stroke.
Conclusion:
Our study provides evidence supporting the causal association between fatigue and the poor functional outcome after ischemic stroke, which emphasizes the importance of implementing interventions aimed at addressing fatigue. This could offer a therapeutic target to improve recovery after ischemic stroke and warrant exploration in a clinical context. One potential mechanism by which fatigue affects functional outcomes after ischemic stroke is through the action of lipid metabolites.
Insights
Genetic liability to fatigue causally links to poor functional outcomes after ischemic stroke. Addressing fatigue may improve stroke recovery, potentially via lipid metabolite pathways. Further clinical research is warranted.
Area of Science:
- Neuroscience
- Genetics
- Metabolomics
Background:
- Fatigue is linked to poorer recovery after ischemic stroke.
- Previous observational studies suggest an association, but causality remains unclear.
Purpose of the Study:
- To investigate the potential causal relationship between fatigue and poor functional outcomes following ischemic stroke using Mendelian randomization (MR).
Main Methods:
- Utilized a two-sample MR approach with genetic instrumental variables for fatigue (36 SNPs from 449,019 individuals) and functional outcomes in ischemic stroke survivors (6,021 individuals).
- Assessed causal effects using inverse variance weighted, MR-Egger, and weighted median methods.
- Explored reverse causality and mediation effects of lipid metabolites via two-step MR analysis.
Main Results:
- Genetic liability to fatigue was causally associated with poor functional outcome (modified Rankin Scale ≥3 at 3 months) after ischemic stroke (OR=4.20, p<0.05).
- No significant association was found between genetically predicted poor functional outcome and fatigue.
- Several lipid metabolites, including cholesteryl esters, VLDL, free cholesterol, phospholipids, and triglycerides, mediated the association between fatigue and poor stroke outcomes.
Conclusions:
- This study provides evidence for a causal link between fatigue and adverse functional outcomes post-ischemic stroke.
- Targeting fatigue presents a potential therapeutic strategy to enhance stroke recovery.
- Lipid metabolites may play a mediating role in the fatigue-stroke outcome relationship.
