Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Abstract

BackgroundHigher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.Methods and FindingsGenome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10−8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10−25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26–1.65, p = 9.5 × 10−8) for isoleucine, 1.85 (95% CI 1.41–2.42, p = 7.3 × 10−6) for leucine, and 1.54 (95% CI 1.28–1.84, p = 4.2 × 10−6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.ConclusionsEvidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.

Myobolites: muscle-derived metabolites with paracrine and systemic effects

“…BCAAs have been implicated in the development of insulin resistance, most notably through strong epidemiological correlations between elevated BCAA levels and insulin resistance 37–40 and rodent studies with supplementation of BCAAs in daily chow or genetic perturbation of BCAA metabolism 41–44 . However, the mechanism by which BCAAs contribute to insulin resistance in not understood.…”

Precision medicine in diabetes: an opportunity for clinical translation

“…45 for methodological details) have implicated BCAAs in the pathogenesis of T2D and suggested that genetically raised insulin resistance drives higher circulating fasting BCAA levels. 80,81 In a recent analysis of 1622 nondiabetic participants from the Framingham Heart Study, the combination of genetics, metabolomics, and clinical factors increased the prediction of future T2D. 82 In brief, a 62-variant GRS showed an area under the curve (AUC) of 64%; addition of metabolites increased the AUC to 82%, and the combination of genetics, metabolomics and clinical factors achieved an AUC of 88%.…”

A Decade of Genetic and Metabolomic Contributions to Type 2 Diabetes Risk Prediction

“…In a subsequent MR analysis, using the PPM1K locus (which encodes a mitochondrial phosphatase that activates branched-chain α-ketoacid dehydrogenase (BCKD)) as a genetic instrument for leucine, isoleucine, and valine, BCAA was implicated in a causal role in the development of T2D [104]. However, given that BCKD has a range of substrates besides leucine, isoleucine, and valine, untangling which one or more of these substrates causes T2D is challenging.…”