title: Is diabetes mellitus-linked amino acid signature associated with β-blocker-induced impaired fasting glucose?
abstract: BACKGROUND
  The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin resistance. We investigated whether this same AA signature, single-nucleotide polymorphisms in genes in their catabolic pathway, was associated with development of impaired fasting glucose (IFG) after atenolol treatment.
  
  
  RESULTS
  Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available for the development of IFG. We assessed the association between baseline circulating levels of isoleucine, leucine, valine, tyrosine, and phenylalanine, as well as single-nucleotide polymorphisms in branched-chain amino-acid transaminase 1 (BCAT1) and phenylalanine hydroxylase (PAH) with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the 5 AAs was associated with the following odds ratio and 95% confidence interval for IFG based on a fully adjusted model: isoleucine 2.29 (1.31-4.01), leucine 1.80 (1.10-2.96), valine 1.77 (1.07-2.92), tyrosine 2.13 (1.20-3.78), and phenylalanine 2.04 (1.16-3.59). The composite P value was 2×10(-5). Those with PAH (rs2245360) AA genotype had the highest incidence of IFG (P for trend=0.0003).
  
  
  CONCLUSIONS
  Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol-associated adverse metabolic effects. Clinical Trial Registration- http://www.clinicaltrials.gov; Unique Identifier: NCT00246519.
authors.affiliation: Department of Pharmacotherapy and Translational Research.
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-Dehoff
authors.forename: Wei
authors.initials: W
authors.lastname: Hou
authors.forename: Liming
authors.initials: L
authors.lastname: Weng
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Baillie
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Mohamed H A
authors.initials: MH
authors.lastname: Shahin
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Arlene
authors.initials: A
authors.lastname: Chapman
authors.forename: John G
authors.initials: JG
authors.lastname: Gums
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Boyle
authors.forename: Hongjie
authors.initials: H
authors.lastname: Zhu
authors.forename: William R
authors.initials: WR
authors.lastname: Wikoff
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Rima
authors.initials: R
authors.lastname: Kaddurah-Daouk
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000097:blood*; D001262:Atenolol / Q000009:adverse effects* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology*; D005215:Fasting / Q000097:blood*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D000596:Amino Acids; D001786:Blood Glucose; D001262:Atenolol
keywords: amino acids; metabolomics; pharmacogenetics