Evaluating the Role of Amino Acids in Type 2 Diabetes Risk: a Mendelian Randomization Study

Background Previous observational and Mendelian randomization studies suggested different amino acids associated with type 2 diabetes (T2D). However, these studies may suffer from confounding or the use of invalid instruments, respectively. Methods We extracted strong ( p < 5×10 - 8 ), independent (r 2 < 0.001) genetic variants associated with nine amino acids (alanine, glutamine, glycine, histidine, phenylalanine, tyrosine, isoleucine, leucine, and valine) from summary statistics of UK Biobank (N ≤ 115,075), with exclusion of potentially pleiotropic variants. We then applied them to T2D summary statistics from DIAMANTE Consortium (without UK Biobank participants) (N = 455,313) and FinnGen study (N = 365,950), and glycemic traits (MAGIC consortium, N ≤ 209,605). Inverse variance weighed (IVW) method was the main analysis, with multiple sensitivity analyses to assess robustness of findings. Results Alanine was associated with higher T2D risk, correcting for multiple testing (Odds Ratio (OR) 1.50 per SD; 95% CI 1.16 to 1.95). At nominal significance, isoleucine was associated with higher T2D risk (OR 1.13; 95% CI 1.00 to 1.27) and tyrosine was associated with lower T2D risk (OR 0.89; 95% CI 0.80 to 0.99). Alanine was also associated with lower insulin, higher glycated hemoglobin and glucose whereas isoleucine and leucine were associated with lower insulin. These associations were consistent in most sensitivity analyses. Conclusion Alaine likely contributed to higher T2D risk whilst the associations for isoleucine and tyrosine requires further verification. Whether these findings explain health effects of sources of amino acids, such as diet, should be further explored.