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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2005-05, Vol.83 (5), p.353-361
• Main Authors: NIELSEN, Eva-Maria D, HANSEN, Lars, STISSING, Trine, YANAGISAWA, Keiko, BORCH-JOHNSEN, Knut, POULSEN, Pernille, VAAG, Allan, HANSEN, Torben, PEDERSEN, Oluf
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Birth Weight - genetics; Case-Control Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p57; Cyclin-Dependent Kinases - genetics; Denmark; Diabetes Mellitus, Type 2 - genetics; DNA Mutational Analysis; Female; General aspects; Genetic Variation; Glucose Tolerance Test; Humans; Insulin - blood; Male; Medical sciences; Middle Aged; Nuclear Proteins - genetics; Polymorphism, Genetic; Promoter Regions, Genetic; Proto-Oncogene Proteins - genetics; Quantitative Trait, Heritable; RNA, Messenger - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-005-0647-3

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.