We estimated the causal role of eIF-4E and S6K plasma proteins, mTOR downstream targets, on type 2 diabetes, based on 16 single nucleotide polymorphisms (SNPs) for eIF-4E and 16 SNPs for S6K at p-value < 5x10-6 . We applied these SNPs per exposure to publically available genetic associations with diabetes from the DIAbestes 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. Sensitivity analysis was conducted using the weighted median, and MR-Egger estimates.
eIF-4E cap-dependent translation factor was associated with lowered risk of type 2 diabetes with an odds ratio (OR) 0.94 per effect size, 95% confidence interval (0.88, 0.99, p=0.03) with similar estimates from the weighted median and MR-Egger. S6K was not associated with diabetes, OR 0.95, 95% confidence interval (0.89, 1.01, p=0.08). Sensitivity analysis using MR-Egger and weighed median analysis did not indicate pleiotropic effects suggesting a unique protective effect of eIF-4E on type 2 diabetes.
This unbiased Mendelian Randomization estimate is consistent with a causally protective association of eIF-4E on type 2 diabetes. eIF-4E may be a target for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes.
Funding Sources : No specific funding