Abstract 16868: Genetic Regulation of Branched-Chain Amino Acid Levels Does Not Increase Type 2 Diabetes Risk

Abstract

Introduction: The branched-chain amino acids (BCAAs) valine, leucine, and isoleucine are associated with incident type 2 diabetes (T2D). Prior genetic studies have provided conflicting results as to whether the BCAAs are causally related to T2D but are limited by a small number of genetic instruments associated with BCAA levels. Hypothesis: We hypothesized that polygenic predictors that capture a broad set of genetic mechanisms regulating BCAA levels would clearly define the etiological relationship with T2D. Methods: We constructed and validated instrumental variables for each BCAA using well-powered datasets and tested their association with T2D using two-sample inverse variance weighted (IWV) Mendelian randomization (MR). Sensitivity analyses were performed to ensure the accuracy of the findings. We also tested whether instrumental variables for T2D, fasting insulin, and body mass index (BMI) were associated with BCAA levels. Finally, logistic regression was used to test whether a polygenic risk score (PRS) for T2D was associated with measured BCAA levels among 1220 participants in the Framingham offspring study (FOS) without prevalent T2D. Results: There were no significant associations with T2D for valine (beta=0.17 change in log-odds per standard deviation change in valine, [95% CI, -0.28 - 0.62], p=0.45), leucine (beta=0.19 [-0.30 - 0.68] p=0.45) or isoleucine (beta=0.02 [-0.54 - 0.59], p=0.94). In contrast, T2D was associated with each BCAA (valine: beta=0.08 per standard deviation change in levels per log-odds change in type 2 diabetes, [0.05 - 0.10], p=1.8x10 -9 ), (leucine: beta= 0.06 [0.04 - 0.09], p=4.5x10 -8 ) and isoleucine (beta= 0.06 [0.04 - 0.08], p=2.8x10 -8 ). The T2D associations were replicated in an independent population but not in a second population where T2D cases were removed. Similarly, a T2D PRS was associated with measured BCAA levels in the FOS study but not when incident T2D cases were removed. Positive associations were seen for fasting insulin and BMI, and the BCAAs by MR, and, in multivariable MR analyses, T2D and fasting insulin had independent associations with each BCAA. Conclusions: These data suggest that BCAAs are not mediators of T2D risk but may rather serve as biomarkers of T2D and higher insulin levels.