Relationship between branched chain amino acids and type 2 diabetes: a bidirectional Mendelian Randomization study

Abstract

Background: Human genetic studies suggest that the branched chain amino acids (BCAA) valine, leucine and isoleucine have a causal association with type 2 diabetes. However, inferences are based on analyses of a limited number of genetic loci associated with BCAAs. Whether these conclusions are supported when using instrumental variables for BCAAs that capture a broad set of genetic mechanisms is not known. Methods: We constructed and validated instrumental variables for each BCAA using large well-powered datasets and tested their association with type 2 diabetes using the two-sample inverse variance weighted (IWV) Mendelian randomization (MR) approach. Sensitivity analyses were performed to ensure the accuracy of the findings. Instrumental variables for type 2 diabetes, fasting insulin and body mass index (BMI) were also tested for associations with BCAA levels. Results: There were no significant associations with diabetes 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, type 2 diabetes 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 type 2 diabetes associations were replicated in an independent population, but not in a second population where type 2 diabetes cases were removed, highlighting the consistency and specificity of the association. Similar positive associations were seen for fasting insulin and BMI with the BCAAs. In multivariable MR analyses, type 2 diabetes and fasting insulin had consistent independent associations with each BCAA. Conclusions: These data suggest that the BCAAs are not mediators of type 2 diabetes risk but are biomarkers of diabetes and higher insulin.

Insights into the metabolic consequences of type 2 diabetes

“…We find no evidence of a causal role of absolute triglycerides (TG) levels on T2D, although it has been described as a predictor of T2D risk 17,42 . We replicate findings from Mosley et al 16 , which do not find evidence of a causal role of BCAAs on the risk of T2D. Almost all of the significant metabolites in the forward direction are also found to be associated in the reverse direction, highlighting the complex interplay between metabolite profiles and T2D liability.…”

“…The limited prediction of metabolite profiles may be related to the uncertain causal role in modulating T2D risk, a question investigated using Mendelian randomization (MR) 12 . One particular example is BCAAs, for which some studies have described a causal effect of valine, leucine and/or isoleucine on T2D [13][14][15] , while more recent evidence has shown no causal effect of BCAAs on T2D risk in the UK Biobank (UKBB) cohort 16 . Conversely, increasing evidence of a causal effect of T2D liability on metabolite profiles has been shown, with increased alanine levels caused by increased T2D liability being consistently reported 13,17,18 .…”

“…We first performed a bi-directional two sample MR analysis, using non-overlapping datasets for the SNP-exposure and SNP-outcome associations to limit potential bias 12 . Previous MR studies performed in the UKBB cohort have used only the first release of data for the 249 metabolites and were either limited to a few metabolites, or only investigated a single causal direction 16,18,26 .…”

“…The present work presents some limitations. We have performed bi-directional MR using a similar framework to previous studies in the UKBB based on the first release dataset of metabolite data 16,18 , with the benefit of providing replication in the second release dataset. The use of the same outcome data for the two release datasets prevented the meta-analysis of the results.…”

Metabolic liability for weight gain in early adulthood

“… 103 , 104 Analogously, while circulating BCAA levels are certainly dysregulated with insulin resistance, their mechanistic-etiologic contribution to this phenotype in humans is still under debate. 105 …”