Abstract:
:The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-sensing pathway is a central regulator of cell growth and metabolism and is dysregulated in diabetes. The eukaryotic translation initiation factor 4E (EIF-4E) protein, a key regulator of gene translation and protein function, is controlled by mTORC1 and EIF-4E Binding Proteins (EIF4EBPs). Both EIF4EBPs and ribosomal protein S6K kinase (RP-S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted EIF-4E, EIF-4A, EIF-4G, EIF4EBP, and RP-S6K circulating levels using Mendelian Randomization. We estimated the causal role of EIF-4F complex, EIF4EBP, and S6K in the circulation on type 2 diabetes, based on independent single nucleotide polymorphisms strongly associated (p = 5 × 10-6) with EIF-4E (16 SNPs), EIF-4A (11 SNPs), EIF-4G (6 SNPs), EIF4EBP2 (12 SNPs), and RP-S6K (16 SNPs). The exposure data were obtained from the INTERVAL study. We applied these SNPs for each exposure to publically available genetic associations with diabetes from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676) and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald-estimates using inverse variance weighting with multiplicative random effects and conducted sensitivity analysis. Mendelian Randomization (MR-Base) R package was used in the analysis. The PhenoScanner curated database was used to identify disease associations with SNP gene variants. EIF-4E is associated with a lowered risk of type 2 diabetes with an odds ratio (OR) 0.94, 95% confidence interval (0.88, 0.99, p = 0.03) with similar estimates from the weighted median and MR-Egger. Similarly, EIF-4A was associated with lower risk of type 2 diabetes with odds ratio (OR) 0.90, 95% confidence interval (0.85, 0.97, p = 0.0003). Sensitivity analysis using MR-Egger and weighed median analysis does not indicate that there is a pleiotropic effect. This unbiased Mendelian Randomization estimate is consistent with a protective causal association of EIF-4E and EIF-4A on type 2 diabetes. EIF-4E and EIF-4A may be targeted for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Soliman GA,Schooling CMdoi
10.1038/s41598-020-71987-8subject
Has Abstractpub_date
2020-09-25 00:00:00pages
15737issue
1issn
2045-2322pii
10.1038/s41598-020-71987-8journal_volume
10pub_type
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