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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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Abstract

CDK4 is involved in the regulation of body weight, pancreatic β-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 β-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.

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Abbreviations

BMI :

Body mass index

BWS :

Beckwith-Wiedemann syndrome

CDK(s) :

Cyclin-dependent kinase(s)

CDK4 :

Cyclin-dependent kinase 4

CDKI(s) :

Cyclin-dependent kinase inhibitor(s)

CI :

Confidence interval

DZ :

Dizygotic

FFM :

Fat-free mass

HI :

Hyperinsulinism of infancy

HOMA :

Homeostasis model of assessment

IVGTT :

Intravenous glucose tolerance test

SSCP :

Single strand conformational polymorphism

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Acknowledgements

The study was supported by the Danish Medical Research Council, the Danish Diabetes Association, the Danish Heart Foundation, and EEC grants (QLRT-1999100546, BMH4-CT98-3084, and QLK-CT-2000-01038). The authors thank Annemette Forman, Inge Lise Wantzin, and Marianne Stendal for dedicated and careful technical assistance, and Grete Lademann for secretarial support.

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Authors and Affiliations

  1. Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Copenhagen, Denmark

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

  2. Science and Medicine, Novo Nordisk A/S, Bagsvaerd, Denmark

    Lars Hansen

  3. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark

    Knut Borch-Johnsen

  4. Faculty of Health Science, University of Aarhus, Aarhus, Denmark

    Knut Borch-Johnsen & Oluf Pedersen

  5. Steno Diabetes Center, Niels Steensens Vej 2, 2820, Gentofte, Copenhagen, Denmark

    Eva-Maria D. Nielsen

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  1. Eva-Maria D. Nielsen
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Correspondence to Eva-Maria D. Nielsen.

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Nielsen, EM.D., Hansen, L., Stissing, T. et al. 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. J Mol Med 83, 353–361 (2005). https://doi.org/10.1007/s00109-005-0647-3

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