Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits

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Eva-Maria D Nielsen, Lars Hansen, Trine Stissing, Keiko Yanagisawa, Knut Borch-Johnsen, Pernille Poulsen, Allan Vaag, Torben Hansen, Oluf Pedersen

CDK4 is involved in the regulation of body weight, pancreatic beta-cell proliferation, insulin responsiveness, and diabetes pathogenesis. CDK4 activity is inhibited by CDKN1C, which is regulated by insulin. In addition, CDKN1C plays an important role in beta-cell proliferation and is involved in the pathogenesis of the Beckwith-Wiedemann syndrome, a disorder characterized by neonatal hyperinsulinaemic hypoglycaemia and pre- and post-natal overgrowth. The aim of this study was to investigate if variations in the proximal promoter and the coding region of the CDKN1C and CDK4 genes are associated with type 2 diabetes or changes in related quantitative phenotypes among glucose-tolerant subjects. Mutation analyses of the two genes in 62 type 2 diabetic patients resulted in the discovery of seven variants of CDKN1C and two variants of CDK4. In a case-control study comprising 717 type 2 diabetic patients and 518 glucose-tolerant subjects the most frequent variants did not show any difference in allele frequencies between the type 2 diabetic patients and the control subjects. However, in two genotype-quantitative trait correlation studies involving 206 glucose-tolerant offspring of type 2 diabetic patients and 359 young, healthy subjects the CDKN1C del171APVA variant associated with increased birth weight (P=0.05 and P=0.05). Furthermore, the same variant tended to be associated with decreased basal glucose oxidation among 16 genotypically discordant dizygotic twins (P=0.03). In a genotype-quantitative trait study involving 500 middle-aged glucose-tolerant subjects the CDK4 IVS2-31G-->A variant was associated with an increased waist circumference (P=0.03) and waist-to-hip ratio (P=0.02) and altered fasting plasma glucose (P=0.03). However, these later findings could not be replicated in additional studies. In conclusion, variants in CDKN1C may contribute to the inter-individual variation in birth weight.
Original languageEnglish
JournalJournal of Molecular Medicine
Volume83
Issue number5
Pages (from-to)353-61
Number of pages9
ISSN0946-2716
DOIs
Publication statusPublished - 2005

    Research areas

  • Aged, Birth Weight, Case-Control Studies, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase Inhibitor p57, Cyclin-Dependent Kinases, DNA Mutational Analysis, Denmark, Diabetes Mellitus, Type 2, Female, Genetic Variation, Glucose Tolerance Test, Humans, Insulin, Male, Middle Aged, Nuclear Proteins, Polymorphism, Genetic, Promoter Regions, Genetic, Proto-Oncogene Proteins, Quantitative Trait, Heritable, RNA, Messenger

ID: 38456671