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Promoter Polymorphism in PCK1 (Phosphoenolpyruvate Carboxykinase Gene) Associated with Type 2 Diabetes Mellitus

Vascular Biology Research Group, Robarts Research Institute, and Department of Medicine (H.C., E.v.d.V., M.R.B., J.G.P., R.A.H.), and Thames Valley Family Practice Research Unit (S.B.H.), University of Western Ontario, London, Ontario, Canada N6A 5K8; and Department of Medicine and Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto (A.J.G.H., B.Z.), and Department of Public Health Sciences, University of Toronto (T.K.Y.), Toronto, Ontario, Canada M5S 1A8

Address all correspondence and requests for reprints to: Dr. Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 100 Perth Drive, Room 406, London, Ontario, Canada N6A 5K8. E-mail: hegele{at}robarts.ca.

We sequenced the promoter and coding regions of PCK1 encoding cytosolic phosphoenolpyruvate carboxykinase from genomic DNA of subjects with type 2 diabetes mellitus (DM). We found nine single nucleotide polymorphisms (SNPs) that were present with varying allele frequencies and pairwise linkage disequilibrium relationships in different ethnic groups. The -232CG promoter SNP was within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription. The expression of a luciferase reporter construct containing -232G in three different cell lines showed significantly increased basal expression with no down-regulation by insulin compared with a construct containing -232C. The odds ratios for type 2 DM among subjects with one or two copies of -232G compared with -232C/C homozygotes were 1.9 (95% confidence interval, 1.2–3.0) in a Canadian aboriginal sample and 2.8 (95% confidence interval, 1.7–4.7) in a Caucasian sample. Thus, we report a promoter SNP in PCK1 that was resistant to down-regulation by insulin in vitro and was associated with type 2 DM in two independent study samples.

This work was supported by grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association (no. 992 in honor of Hazel E. Kerr), the Canadian Genetic Diseases Network, and the Blackburn Group.

S.B.H. is a Career Scientist with the Ontario Ministry of Health.

T.K.Y. is a Senior Investigator with the Canadian Institutes of Health Research.

J.G.P. and R.A.H. are Career Investigators with the Heart and Stroke Foundation of Ontario.

R.A.H. holds a Canada Research Chair (Tier I) in Human Genetics.

Abbreviations: BMI, Body mass index; C/EBP, CCAAT/enhancer-binding protein; CI, confidence interval; db, National Center for Biotechnology Information database; DM, diabetes mellitus; IRS, insulin response sequence; LD, linkage disequilibrium; nt, nucleotide; OR, odds ratio; PCK1, phosphoenolpyruvate carboxykinase gene; PGC-1, PPAR coactivator-1; RLU, reporter luciferase units; SNP, single nucleotide polymorphism; SSCP, single strand conformation polymorphism.

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