Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits.
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.
Hegele
Robert A
RA
Robarts Research Institute, London, Ontario, Canada. hegele@robarts.ca
Al-Shali
Khalid Z
KZ
House
Andrew A
AA
Hanley
Anthony J G
AJ
Harris
Stewart B
SB
Mamakeesick
Mary
M
Fenster
Aaron
A
Zinman
Bernard
B
Cao
Henian
H
Spence
J David
JD
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
C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases