title: A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.
abstract: OBJECTIVE
  To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity.
  
  
  METHODS
  A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies.
  
  
  RESULTS
  Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001).
  
  
  CONCLUSIONS
  A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies.
authors.affiliation: Department of Pediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand; Discipline of Pediatrics and Robinson Institute, University of Adelaide, Adelaide, Australia. Electronic address: esko.wiltshire@otago.ac.nz.
authors.forename: Esko J
authors.initials: EJ
authors.lastname: Wiltshire
authors.affiliation: Discipline of Pediatrics and Robinson Institute, University of Adelaide, Adelaide, Australia; Diabetes and Endocrinology Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Alexia S
authors.initials: AS
authors.lastname: Peña
authors.affiliation: Discipline of Pediatrics and Robinson Institute, University of Adelaide, Adelaide, Australia; Diabetes and Endocrinology Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: MacKenzie
authors.affiliation: Genetics and Molecular Pathology Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Tulika
authors.initials: T
authors.lastname: Bose-Sundernathan
authors.affiliation: Medical Imaging, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Roger
authors.initials: R
authors.lastname: Gent
authors.affiliation: Discipline of Pediatrics and Robinson Institute, University of Adelaide, Adelaide, Australia; Diabetes and Endocrinology Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Couper
mesh_terms: D000293:Adolescent; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D063766:Pediatric Obesity / Q000235:genetics* / Q000503:physiopathology*; D011110:Polymorphism, Genetic
chemical_list: D005492:Folic Acid; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III