title: Pharmacogenetic influence of eNOS gene variant on endothelial and glucose metabolism responses to L-arginine supplementation: Post hoc analysis of the L-arginine trial.
abstract: OBJECTIVE
  To evaluate whether variants of the eNOS gene are associated with endothelial and metabolic responses to L-arginine (L-arg) supplementation.
  
  
  METHODS
  We examined a single nucleotide polymorphism of the eNOS gene (rs753482-A>C) to investigate the effects of this variant on endothelial function (EF), colony-forming unit-endothelial cell (CFU-EC) number, asymmetric-dimethylarginine (ADMA) level, insulin sensitivity index (ISI), and insulin secretion (IS) in a post hoc analysis of the L-arg trial. The L-arg trial (6.4 g/day for 18 months) was a single-center, randomized, double-blind, parallel-group, placebo-controlled, phase III trial in individuals with impaired glucose tolerance and metabolic syndrome. followed by a 12-month extended follow-up period after termination of the study drug (NCT 00917449).
  
  
  RESULTS
  At baseline, EF, CFU-EC numbers, ADMA levels, and ISI were impaired in subjects carrying minor allele C (both heterozygotes, AC and homozygotes, CC) as compared to subjects carrying major allele A (homozygotes, AA) (p<0.01). Compared to placebo, L-arg increased EF, CFU-EC numbers, and ISI, and improved ADMA levels and IS (p<0.01). The greatest improvements were found in AA subjects treated with L-arg, while the worst results were found in AC+CC subjects treated with placebo. In the placebo-treated subjects, EF, CFU-EC, ISI, and IS were significantly lower and ADMA was significantly higher in AC+CC subjects than in AA subjects.
  
  
  CONCLUSIONS
  Treatment with L-arg induced similar improvements in EF, CFU-EC numbers, ADMA levels, ISI, and IS in both AA subjects and AC+CC subjects. The presence of minor allele resulted in the worst prognosis in terms of EF, CFU-EC numbers, ADMA levels, ISI, and IS during the 30-month observation period.
authors.affiliation: Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy. Electronic address: monti.lucilla@hsr.it.
authors.forename: Lucilla D
authors.initials: LD
authors.lastname: Monti
authors.affiliation: Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Galluccio
authors.affiliation: Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fontana
authors.affiliation: Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Spadoni
authors.affiliation: Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Comola
authors.affiliation: Vascular Surgery, Cardio-Thoraco-Vascular Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Massimiliano M
authors.initials: MM
authors.lastname: Marrocco Trischitta
authors.affiliation: Vascular Surgery, Cardio-Thoraco-Vascular Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
authors.affiliation: Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy; Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bosi
authors.affiliation: Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine,IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Piermarco
authors.initials: P
authors.lastname: Piatti
mesh_terms: D001120:Arginine / Q000008:administration & dosage*; D004311:Double-Blind Method; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010597:Pharmacogenetics; D010919:Placebos; D020641:Polymorphism, Single Nucleotide
chemical_list: D010919:Placebos; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D005947:Glucose
keywords: Insulin Secretion; Insulin Sensitivity; L-Arginine; Pharmacogenetics; eNOS polymorphism