PLoS Medicine (Nov 2016)

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

  • 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

DOI
https://doi.org/10.1371/journal.pmed.1002179
Journal volume & issue
Vol. 13, no. 11
p. e1002179

Abstract

Read online

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 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.