Abstract
Cyclin-dependent kinase inhibitor-2A/B (CDKN2A/B) has been reported as a candidate gene of type 2 diabetes (T2D) based on its chromosomal position and its important role in β-cell function and regeneration. However, studies to date have reported inconsistent findings regarding the association between T2D and CDKN2A/B. To clarify this inconsistence, we conducted a meta-analysis based on alleles and genotypes prevalence of rs10811661 and rs564398 in CDKN2A/B. The PubMed, EMBASE, and Medline databases were systematically reviewed for studies published between January, 2006, and November, 2010. A total of 35 reports were collected, among of them only 16 studies (including 24,407 cases and 33,937 controls) match the inclusion criteria and were selected for the statistical test. In the meta-analysis of published data, our results suggest that the rs10811661 T allele (OR 1.28, 95% CI 1.21–1.36, P < 1 × 10−5) and TT genotype (OR 1.32, 95% CI 1.22–1.43, P < 1 × 10−5) of CDKN2A/B were associated with type 2 diabetes respectively, but rs564398 was not (for allele only: OR 0.96, 95% CI 0.88–1.05, P = 0.35). The association between rs10811661 T allele and T2D was observed both in Asia (P < 1 × 10−4) and Europe ethnicity groups (P = 0.002). This meta-analysis yielded evidence that rs10811661 of CDKN2A/B confers risk for T2D. Larger studies with mixed ethnicity subjects are required to validate our findings.
Similar content being viewed by others
References
van Hoek M, Dehghan A, Witteman JC et al (2008) Predicting type 2 diabetes based on polymorphisms from genome-wide association studies. Diabetes 57:2911–2914
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, Novartis Institutes of BioMedical Research (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336
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 316:1336–1341
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 316:1341–1345
Sandhu MS, Weedon MN, Fawcett KA et al (2007) Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 39:951–953
Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885
Steinthorsdottir V, Thorleifsson G, Reynisdottir I et al (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775
Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14000 cases of seven common diseases and 3000 shared controls. Nature 447:661–678
Gudmundsson J, Sulem P, Steinthorsdottir V et al (2007) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 39:977–983
Frayling TM, Timpson NJ, Weedon MN et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894
Krishnamurthy J, Ramsey MR, Ligon KL et al (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457
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 22:44–52
Mettus RV, Rane SG (2003) Characterization of the abnormal pancreatic development, reduced growth and infertility in Cdk4 mutant mice. Oncogene 22:8413–8421
Marzo N, Mora C, Fabregat ME et al (2004) Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knockin 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 47:686–694
Tsutsui T, Hesabi B, Moons DS et al (1999) Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity. Mol Cell Biol 19:7011–7019
Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127:265–275
Meigs JB, Shrader P, Sullivan LM et al (2008) Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 359:2208–2219
Herder C, Rathmann M, Strassburger K et al (2008) Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 genes confer risk of type 2 diabetes independently of BMI in the German KORA studies. Horm Metab Res 40:722–726
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Deeks JJ (2001) Systematic reviews in health care: systematic reviews of evaluations of diagnostic and screening tests. BMJ 323:157–162
Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191
Grarup N, Rose CS, Andersson EA et al (2007) Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10, 705 Danish subjects validation and extension of genome-wide association studies. Diabetes 56:3105–3111
Ng MC, Park KS, Oh B et al (2008) Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes 57:2226–2233
Wu Y, Li H, Loos RJ et al (2008) Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 57:2834–2842
Rong R, Hanson RL, Ortiz D et al (2009) Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in pima Indians. Diabetes 58:478–488
Tabara Y, Osawa H, Kawamoto R et al (2009) Replication study of candidate genes associated with type 2 diabetes based on genome-wide screening. Diabetes 58:493–498
Lee YH, Kang ES, Kim SH et al (2008) Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. J Hum Genet 53:991–998
Tan JT, Ng DP, Nurbaya S et al (2010) Polymorphisms identified through genome-wide association studies and their associations with type 2 diabetes in Chinese, Malays, and Asian-Indians in Singapore. J Clin Endocrinol Metab 95:390–397
Horikawa Y, Miyake K, Yasuda K et al (2008) Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan. J Clin Endocrinol Metab 93:3136–3141
Hu C, Zhang R, Wang C et al (2009) PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a Chinese population. PLoS One 4:e7643
Wen J, Rönn T, Olsson A et al (2010) Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibility genes in a Han Chinese cohort. PLoS One 5:e9153
Han X, Luo Y, Ren Q et al (2010) Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in type 2 diabetes in a Chinese population. BMC Med Genet 11:81
Lin Y, Li P, Cai L et al (2010) Association study of genetic variants in eight genes/loci with type 2 diabetes in a Han Chinese population. BMC Med Genet 11:97
Duesing K, Fatemifar G, Charpentier G et al (2008) Strong association of common variants in the CDKN2A/CDKN2B region with type 2 diabetes in French Europids. Diabetologia 51:821–826
Cho YM, Kim TH, Lim S et al (2009) Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population. Diabetologia 52:253–261
Qu HQ, Grant SF, Bradfield JP et al (2008) Association analysis of type 2 diabetes loci in type 1 diabetes. Diabetes 57:1983–1986
Takeuchi F, Serizawa M, Yamamoto K et al (2009) Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 58:1690–1699
Acknowledgments
This work was supported by grants from Chongqing Medical University (No. 0124418029, No. XBZD200701), Natural Science Foundation Project of CQ CSTC (No. 2008BB5074) and The Program for Excellent Talents of University in Chongqing Municipality. We also thank the anonymous reviewers who made comments valuable to the revision of this article.
Conflict of interest statement
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bao, X.Y., Xie, C. & Yang, M.S. Association between Type 2 Diabetes and CDKN2A/B: a meta-analysis study. Mol Biol Rep 39, 1609–1616 (2012). https://doi.org/10.1007/s11033-011-0900-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-011-0900-5