Disparate Associations of a Functional Promoter Polymorphism in PCK1 With Carotid Wall Ultrasound Traits

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Abstract
Background and Purpose— 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.