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

Summary

Background Higher 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 Findings Genome-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. Conclusions Evidence 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.

Key Points

• 1Higher BCAA levels are associated with increased type Two diabetes risk
• 2Mendelian randomisation was used to assess the causal relationship
• 3Genetic analyses involved over 47,000 type Two diabetes cases and 267,000 controls
• 4The study identifies five genomic regions linked to BCAA levels
• 5Findings imply potential targets for diabetes intervention through BCAA metabolism.

Related articles

• Neonatal Disorders

  This document provides a comprehensive overview of neonatal disorders, including case scenarios and learning objectives targeted at third-year medical students. It outlines essential management plans and assessment procedures for common neonatal conditions.

• 13. Gross Anatomy: Muscles of the Hand

  This document outlines the anatomy of the intrinsic muscles of the hand, detailing their compartments and clinical significance, particularly in relation to carpal tunnel syndrome and recurrent branch injuries.

• 12. Gross Anatomy: RA Upper Extremities

  This document outlines a detailed guide on gross anatomy focused on the upper extremities, covering the shoulder, humerus, elbow, forearm, and hand/wrist series with an emphasis on radiographic examination techniques and anatomical considerations.

• 11. Gross Anatomy: Compartments of the Forearm

  This document outlines the anatomy of the forearm, detailing the anterior and posterior compartments, including the muscles, their origins, insertions, innervation, and actions. It serves as a comprehensive guide for students studying gross anatomy.

• 10. Gross Anatomy: Bones and Muscles of the Shoulder and Arm

  This document outlines the anatomy of the shoulder and arm, including details on the muscles and bones, their origins, insertions, innervations, and primary actions. It provides learning objectives that aim to enhance students' understanding of arm anatomy.