title: Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits.
abstract: OBJECTIVE
  Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), encoded by PCK1, catalyzes the first committed step in gluconeogenesis. We previously showed that a -232C>G promoter polymorphism within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription results in loss of negative regulation by insulin, contributing to worsened metabolic control in the context of insulin resistance. We hypothesized that this polymorphism would be associated with carotid atherosclerosis in a sample of 150 aboriginal Canadians.
  
  
  METHODS
  Dependent variables were 2 distinct carotid traits, namely intima-media thickness (IMT) assessed using B-mode ultrasound and total carotid plaque volume (TPV) assessed using 3D ultrasound.
  
  
  RESULTS
  Multivariate analysis showed significant but opposite associations of PCK1 genotype with these traits. Specifically, subjects with the PCK1-232G/G genotype had more carotid IMT (0.80+/-0.02 versus 0.73+/-0.03 mm; P=0.007) but less TPV (0.10+/-0.09 versus 0.38+/-0.13; P=0.03) than subjects with other genotypes.
  
  
  CONCLUSIONS
  The findings connect the key enzyme in gluconeogenesis with atherosclerosis. The meaning of the opposing associations of PCK1 genotype with IMT and TPV is unclear; more work is required to confirm whether these might be distinct quantitative traits with different biological determinants.
authors.affiliation: Robarts Research Institute, London, Ontario, Canada. hegele@robarts.ca
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Khalid Z
authors.initials: KZ
authors.lastname: Al-Shali
authors.forename: Andrew A
authors.initials: AA
authors.lastname: House
authors.forename: Anthony J G
authors.initials: AJ
authors.lastname: Hanley
authors.forename: Stewart B
authors.initials: SB
authors.lastname: Harris
authors.forename: Mary
authors.initials: M
authors.lastname: Mamakeesick
authors.forename: Aaron
authors.initials: A
authors.lastname: Fenster
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: J David
authors.initials: JD
authors.lastname: Spence
mesh_terms: D000293:Adolescent; D000328:Adult; D002170:Canada; D002339:Carotid Arteries / Q000000981:diagnostic imaging*; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D002648:Child; D003920:Diabetes Mellitus / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005943:Gluconeogenesis / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics; D007198:Indians, North American / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012737:Sex Factors; D016037:Single-Blind Method; D017539:Tunica Intima / Q000000981:diagnostic imaging*; D014463:Ultrasonography
chemical_list: C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases