Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study
Javier Amador-Casta?eda, BHS, RRT, FCCM
| Respiratory Care Practitioner | Author | Speaker | Veteran | ESICM Representative, North America
Zhou, K., Yang, H., Xie, Z. et al. Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study. BMC Pharmacol Toxicol 25, 1 (2024). https://doi.org/10.1186/s40360-023-00718-2
Summary of "Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a Mendelian randomisation study"
Summary:
This study investigates the potential causal relationship between antihyperglycemic drugs and epilepsy using Mendelian randomisation (MR). Analyzing genetic variants associated with 74 diabetes medications, the study identified three drug target genes (ETFDH, CYP21A2, CYP2D6) with significant associations to epilepsy risk. While ETFDH and CYP21A2 were linked to an increased risk of epilepsy, CYP2D6 appeared to have protective effects. Metformin, an inhibitor of the ETFDH gene, showed potential as an antiepileptic agent. These findings suggest opportunities for drug repurposing and highlight the need for further clinical trials.
Key Points:
1. ETFDH as a Risk Gene: ETFDH gene variants were associated with an increased risk of epilepsy in both discovery and replication cohorts.
2. CYP21A2 Association: This gene was also linked to higher epilepsy risk, indicating possible interactions with seizure-related pathways.
3. CYP2D6 Protective Effects: Variants in the CYP2D6 gene were inversely associated with epilepsy, suggesting neuroprotective mechanisms.
4. Role of Metformin: As an ETFDH inhibitor, metformin demonstrated antiepileptic effects in animal models and some clinical trials, warranting further investigation.
5. Drug Repurposing Potential: Findings support exploring antihyperglycemic drugs, particularly metformin, as therapeutic options for epilepsy.
6. Mendelian Randomisation Validity: MR analysis avoided confounding and reverse causality issues, strengthening the evidence for causal associations.
7. Implications for Alzheimer’s and Aging: ETFDH’s role in neurodegenerative diseases, such as Alzheimer’s, further validates its significance in neurological conditions.
8. FinnGen and ILAE Data Robustness: Results were consistent across large-scale genome-wide datasets, reinforcing the reliability of the findings.
9. Limitations: The study focused on European populations and genetic long-term effects, limiting the generalizability and relevance to short-term drug responses.
10. Future Research Needs: Further randomized controlled trials (RCTs) are needed to confirm these findings and explore the clinical applications of antihyperglycemic drugs for epilepsy.
Conclusion:
The study identifies ETFDH as a potential risk gene for epilepsy and suggests metformin as a candidate for repurposing as an antiepileptic drug. These findings contribute to the understanding of diabetes-epilepsy interactions and support further clinical exploration of antihyperglycemic drugs in epilepsy treatment.
Watch the following video on"Genetic Testing for the Epilepsies: A New Practice Guideline" by National Society of Genetic Counselors
Discussion Questions:
1. How can future RCTs validate the therapeutic potential of metformin in epilepsy, and what challenges might arise in their design?
2. What are the implications of identifying CYP21A2 and CYP2D6 for personalized epilepsy treatment?
3. How might the findings influence broader strategies for drug repurposing in neurological diseases?
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