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

Authors :
Luca A Lotta
Robert A Scott
Stephen J Sharp
Stephen Burgess
Jian'an Luan
Therese Tillin
Amand F Schmidt
Fumiaki Imamura
Isobel D Stewart
John R B Perry
Luke Marney
Albert Koulman
Edward D Karoly
Nita G Forouhi
Rasmus J O Sjögren
Erik Näslund
Juleen R Zierath
Anna Krook
David B Savage
Julian L Griffin
Nishi Chaturvedi
Aroon D Hingorani
Kay-Tee Khaw
Inês Barroso
Mark I McCarthy
Stephen O'Rahilly
Nicholas J Wareham
Claudia Langenberg
Source :
PLoS Medicine, Vol 13, Iss 11, p e1002179 (2016)
Publication Year :
2016
Publisher :
Public Library of Science (PLoS), 2016.

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.

Subjects

Subjects :
Medicine

Details

Language :
English
ISSN :
15491277 and 15491676
Volume :
13
Issue :
11
Database :
Directory of Open Access Journals
Journal :
PLoS Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.83944e1595d0460791be9b9ab3a376df
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pmed.1002179