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Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a
Ghada A Soliman1, C Mary Schooling2,3
1Department of Environmental, Occupational and Geospatial Health Sciences, The City University of New York, Graduate School of Public Health and Health Policy, 55 West 125th St, New York, NY, 10027, USA. ghada.soliman@sph.cuny.edu.
Scientific Reports
|September 26, 2020
Summary
Genetically predicted higher levels of eukaryotic translation initiation factor 4E (EIF-4E) and EIF-4A are associated with a reduced risk of type 2 diabetes. These findings suggest EIF-4E and EIF-4A as potential therapeutic targets for diabetes prevention.
Area of Science:
- Genetics
- Metabolic Diseases
- Molecular Biology
Background:
- The mammalian Target of Rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism, and its dysregulation is linked to diabetes.
- Eukaryotic translation initiation factor 4E (EIF-4E) is controlled by mTORC1 and plays a crucial role in gene translation.
- EIF4EBPs and RP-S6K are downstream effectors of mTORC1, regulating independent pathways involved in cellular processes.
Purpose of the Study:
- To investigate the causal relationship between genetically predicted circulating levels of EIF-4E, EIF-4A, EIF-4G, EIF4EBP, and RP-S6K and the risk of type 2 diabetes.
- To estimate the causal role of the EIF-4F complex, EIF4EBP, and S6K in circulation on type 2 diabetes using Mendelian Randomization.
Main Methods:
- Mendelian Randomization (MR) analysis was employed using single nucleotide polymorphisms (SNPs) strongly associated with EIF-4E, EIF-4A, EIF-4G, EIF4EBP2, and RP-S6K.
- Exposure data were derived from the INTERVAL study, and genetic associations with type 2 diabetes were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium.
- SNP-specific estimates were meta-analyzed using inverse variance weighting, with sensitivity analyses conducted using weighted median and MR-Egger methods.
Main Results:
- Genetically predicted higher circulating levels of EIF-4E were associated with a significantly lower risk of type 2 diabetes (OR 0.94, p=0.03).
- Similarly, higher genetically predicted EIF-4A levels were associated with a reduced risk of type 2 diabetes (OR 0.90, p=0.0003).
- Sensitivity analyses did not indicate significant pleiotropic effects, supporting the robustness of the findings.
Conclusions:
- The study provides evidence for a protective causal association of EIF-4E and EIF-4A with type 2 diabetes.
- Targeting EIF-4E and EIF-4A, potentially through repurposing existing therapeutics, may represent a novel strategy for reducing type 2 diabetes risk.
- These findings highlight the role of translation initiation factors in metabolic health and diabetes pathogenesis.
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