title: Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Lotta
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen J
authors.identifier: http://orcid.org/0000-0003-2375-1440
authors.initials: SJ
authors.lastname: Sharp
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen
authors.identifier: http://orcid.org/0000-0001-5365-8760
authors.initials: S
authors.lastname: Burgess
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.affiliation: Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom.
authors.forename: Therese
authors.initials: T
authors.lastname: Tillin
authors.affiliation: Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom.
authors.forename: Amand F
authors.identifier: http://orcid.org/0000-0003-1327-0424
authors.initials: AF
authors.lastname: Schmidt
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Fumiaki
authors.identifier: http://orcid.org/0000-0002-6841-8396
authors.initials: F
authors.lastname: Imamura
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Isobel D
authors.initials: ID
authors.lastname: Stewart
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Luke
authors.identifier: http://orcid.org/0000-0001-8117-8246
authors.initials: L
authors.lastname: Marney
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Albert
authors.identifier: http://orcid.org/0000-0001-9998-051X
authors.initials: A
authors.lastname: Koulman
authors.affiliation: Metabolon, Morrisville, North Carolina, United States of America.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Karoly
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nita G
authors.initials: NG
authors.lastname: Forouhi
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rasmus J O
authors.identifier: http://orcid.org/0000-0002-0640-8504
authors.initials: RJ
authors.lastname: Sjögren
authors.affiliation: Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.identifier: http://orcid.org/0000-0002-0166-6344
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0002-0891-0258
authors.initials: A
authors.lastname: Krook
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.|Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom.
authors.forename: Nishi
authors.identifier: http://orcid.org/0000-0002-6211-2775
authors.initials: N
authors.lastname: Chaturvedi
authors.affiliation: Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, United Kingdom.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.|Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
authors.forename: Inês
authors.identifier: http://orcid.org/0000-0001-5800-4520
authors.initials: I
authors.lastname: Barroso
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Mark I
authors.identifier: http://orcid.org/0000-0002-4393-0510
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nicholas J
authors.identifier: http://orcid.org/0000-0003-1422-2993
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
mesh_terms: D000328:Adult; D000368:Aged; D000597:Amino Acids, Branched-Chain / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors; D013548:Sweden; D055815:Young Adult
chemical_list: D000597:Amino Acids, Branched-Chain