Branched‐chain amino acids and type 2 diabetes: a bidirectional Mendelian randomization analysis

Abstract Objective Genetic studies have suggested that the branched‐chain amino acids (BCAAs) valine, leucine, and isoleucine have a causal association with type 2 diabetes (T2D). However, inferences are based on a limited number of genetic loci associated with BCAAs. Methods Instrumental variables (IVs) for each BCAA were constructed and validated using large well‐powered data sets and their association with T2D was tested using a two‐sample inverse‐variance weighted Mendelian randomization approach. Sensitivity analyses were performed to ensure the accuracy of the findings. A reverse association was assessed using instrumental variables for T2D. Results Estimated effect sizes between BCAA IVs and T2D, excluding outliers, were as follows: valine (β = 0.14 change in log‐odds per SD change in valine, 95% CI: −0.06 to 0.33, p = 0.17), leucine (β = 0.15, 95% CI: −0.02 to 0.32, p = 0.09), and isoleucine (β = 0.13, 95% CI: −0.08 to 0.34, p = 0.24). In contrast, T2D IVs were positively associated with each BCAA, i.e., valine (β = 0.08 per SD change in levels per log‐odds change in T2D, 95% CI: 0.05 to 0.10, p = 1.8 × 10 −9 ), leucine (β = 0.06, 95% CI: 0.04 to 0.09, p = 4.5 × 10 −8 ), and isoleucine (β = 0.06, 95% CI: 0.04 to 0.08, p = 2.8 × 10 −8 ). Conclusions These data suggest that the BCAAs are not mediators of T2D risk but are biomarkers of diabetes.