nach oben

Erschienen in:

01.05.2008 | Short Communication

Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids

verfasst von: K. Duesing, G. Fatemifar, G. Charpentier, M. Marre, J. Tichet, S. Hercberg, B. Balkau, P. Froguel, F. Gibson

Erschienen in: Diabetologia | Ausgabe 5/2008

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus.

Methods

We genotyped 20 single nucleotide polymorphisms (SNPs) spanning the CDKN2A/CDKN2B locus in our type 2 diabetes case-control cohort. The association between CDKN2A/CDKN2B SNPs and quantitative metabolic traits was also examined in the normoglycaemic participants comprising the control cohort.

Results

We report replication of the strong association of rs10811661 with type 2 diabetes found in the GWASs (\( p = 3.8 \times 10^{ - 7} \); OR 1.43 [95% CI 1.24–1.64]). The other CDKN2A/CDKN2B susceptibility variant, rs564398, did not attain statistical significance (p = 0.053; OR 1.11 [95% CI 1.00–1.24]) in the present study. We also obtained several additional nominal association signals (p < 0.05) at the CDKN2A/CDKN2B locus; however, only the rs3218018 result (p = 0.002) survived Bonferroni correction for multiple testing (adjusted p = 0.04).

Conclusions/interpretation

Our comprehensive association study of common variation spanning the CDKN2A/CDKN2B locus confirms the strong association between the distal susceptibility variant rs10811661 and type 2 diabetes in the French population. Further genetic and functional studies are required to identify the aetiological variants at this locus and determine the cellular and physiological mechanisms by which they act to modulate type 2 diabetes susceptibility.

Nur mit Berechtigung zugänglich

Marzo N, Mora C, Fabregat ME et al (2004) Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knock-in mice have significantly increased beta cell mass and are physiologically functional, indicating that Cdk4 is a potential target for pancreatic beta cell mass regeneration in type 1 diabetes. Diabetologia 47:686–694PubMedCrossRef

Mettus RV, Rane SG (2003) Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Oncogene 22:8413–8421PubMedCrossRef

Rane SG, Dubus P, Mettus RV et al (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia. Nat Genet 22:44–52PubMedCrossRef

Krishnamurthy J, Ramsey MR, Ligon KL et al (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457PubMedCrossRef

Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336PubMedCrossRef

Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345PubMedCrossRef

Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341PubMedCrossRef

Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885PubMedCrossRef

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 26(Suppl 1):S5–S20

10.

Vionnet N, Hani EH, Dupont S et al (2000) Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21–q24. Am J Hum Genet 67:1470–1480PubMedCrossRef

11.

Hercberg S, Preziosi P, Briancon S et al (1998) A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study—design, methods, and participant characteristics. SUpplementation en VItamines et Mineraux AntioXydants. Control Clin Trials 19:336–351PubMedCrossRef

12.

Balkau B (1996) An epidemiologic survey from a network of French Health Examination Centres (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome. Rev Epidemiol Sante Publique 44:373–375 [Article in French]PubMed

13.

Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19:149–150PubMedCrossRef

14.

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRef

15.

Jurinke C, van den Boom D, Cantor CR, Koster H (2002) Automated genotyping using the DNA MassArray technology. Methods Mol Biol 187:179–192PubMed

16.

Barrett JC, Cardon LR (2006) Evaluating coverage of genome-wide association studies. Nat Genet 38:659–662PubMedCrossRef

17.

de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223PubMedCrossRef

Titel: Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids
verfasst von: K. Duesing
G. Fatemifar
G. Charpentier
M. Marre
J. Tichet
S. Hercberg
B. Balkau
P. Froguel
F. Gibson
Publikationsdatum: 01.05.2008
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 5/2008
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-008-0973-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids