title: Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus.
abstract: 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 -232C-->G 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.
authors.affiliation: Vascular Biology Research Group, Robarts Research Institute, and Department of Medicine, University of Western Ontario, London, Ontario, Canada N6A 5K8.
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Eric
authors.initials: E
authors.lastname: van der Veer
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Ban
authors.forename: Anthony J G
authors.initials: AJ
authors.lastname: Hanley
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.forename: Stewart B
authors.initials: SB
authors.lastname: Harris
authors.forename: T Kue
authors.initials: TK
authors.lastname: Young
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000328:Adult; D001483:Base Sequence / Q000235:genetics; D002170:Canada; D003596:Cytosine; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006147:Guanine; D006720:Homozygote; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D006147:Guanine; D003596:Cytosine; D004247:DNA; D010729:Phosphoenolpyruvate Carboxykinase (GTP)