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Replication study of novel risk variants in six genes with type 2 diabetes and related quantitative traits in the Han Chinese lean individuals

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Abstract

To replicating the associations of type 2 diabetes (T2D) and six novel reported variants in Han Chinese lean individuals of first episode T2D, a total of six high risk single nucleotide polymorphisms (SNPs) from the BCL11A, DUSP9, IRS1, CENTD2, ADRA2A, and CDKAL1 genes were examined. Candidate six SNPs were genotyped in 761 T2D patients and 433 control subjects, and associations between the six SNPs and Body Mass Index (BMI), Fasting Plasma Glucose (FPG) and Two Hours Oral Glucose Tolerance Test (2hOGTT) were also investigated. CDKAL1 provided the strongest evidence for replication, where rs7754840 was associated with T2D (odds ratio = 1.54, per copy of the risk C allele, P = 8.10 × 10−7). SNP rs5945326 at DUSP9 showed modest significance (odds ratio = 0.81, per copy of the protective G allele, P = 0.02). After adjusting the confounders of age, gender and BMI, the above results remain significant for both rs7754840 (P < 1.0 × 10−4) and rs5945326 (P = 0.043) respectively. After correcting for multiple testing, however, only the association between T2D and rs7754840 at CDKAL1 (P < 1×10−4) remains significant. In addition, the risk C allele of CDKAL1 rs7754840 was significantly associated with increased FPG levels (P = 3.8 × 10−4). The association between genetic variant in CDKAL1 gene was detected in the Han Chinese lean individuals. The correlation between rs7754840-C allele and increased FPG levels is consistent with the potential function of CDKAL1 gene in pancreatic islets.

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References

  1. Stumvoll M, Goldstein BJ, van Haeften TW (2005) Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365:1333–1346

    Article  PubMed  CAS  Google Scholar 

  2. Yang W, Lu J, Weng J et al (2010) China National Diabetes and Metabolic Disorders Study Group. Prevalence of diabetes among men and women in China. N Engl J Med 362:1090–1101

    Article  PubMed  CAS  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. Shu XO, Long J, Cai Q et al (2010) Identification of new genetic risk variants for type 2 diabetes. PLoS Genet 6:e1001127

    Article  Google Scholar 

  5. Yamauchi T, Hara K, Maeda S et al (2010) A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A–C2CD4B. Nat Genet 42:864–868

    Article  PubMed  CAS  Google Scholar 

  6. Voight BF, Scott LJ, Steinthorsdottir V et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589

    Article  PubMed  CAS  Google Scholar 

  7. Qi L, Cornelis MC, Kraft P et al (2010) Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19:2706–2715

    Article  PubMed  CAS  Google Scholar 

  8. Tsai FJ, Yang CF, Chen CC et al (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6:e1000847

    Article  PubMed  Google Scholar 

  9. Rung J, Cauchi S, Albrechtsen A et al (2009) Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41:1110–1115

    Article  PubMed  CAS  Google Scholar 

  10. 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

    Article  PubMed  CAS  Google Scholar 

  11. Timpson NJ, Lindgren CM, Weedon MN et al (2009) Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58:505–510

    Article  PubMed  CAS  Google Scholar 

  12. Unoki H, Takahashi A, Kawaguchi T et al (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40:1098–1102

    Article  PubMed  CAS  Google Scholar 

  13. Yasuda K, Miyake K, Horikawa Y et al (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40:1092–1097

    Article  PubMed  CAS  Google Scholar 

  14. Zeggini E, Scott LJ, Saxena R et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645

    Article  PubMed  CAS  Google Scholar 

  15. Florez JC, Manning AK, Dupuis J et al (2007) A 100 K genome-wide association scan for diabetes and related traits in the Framingham Heart Study: replication and integration with other genome-wide datasets. Diabetes 56:3063–3074

    Article  PubMed  CAS  Google Scholar 

  16. Hanson RL, Bogardus C, Duggan D et al (2007) A search for variants associated with young-onset type 2 diabetes in American Indians in a 100 K genotyping array. Diabetes 56:3045–3052

    Article  PubMed  CAS  Google Scholar 

  17. Rampersaud E, Damcott CM, Fu M et al (2007) Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes 56:3053–3062

    Article  PubMed  CAS  Google Scholar 

  18. Salonen JT, Uimari P, Aalto JM et al (2007) Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium. Am J Hum Genet 81:338–345

    Article  PubMed  CAS  Google Scholar 

  19. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 447:661–678

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. 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

    Article  PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. 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

    Article  PubMed  CAS  Google Scholar 

  24. Hayes MG, Pluzhnikov A, Miyake K et al (2007) Identification of type 2 diabetes genes in Mexican Americans through genome-wide association studies. Diabetes 56:3033–3044

    Article  PubMed  CAS  Google Scholar 

  25. Fukushima M, Suzuki H, Seino Y (2004) Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes. Diabetes Res Clin Pract 66(Suppl 1):S37–S43

    Article  PubMed  CAS  Google Scholar 

  26. Rosengren AH, Jokubka R, Tojjar D et al (2010) Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327:217–220

    Article  PubMed  CAS  Google Scholar 

  27. Gribble FM (2010) Alpha2A-adrenergic receptors and type 2 diabetes. N Engl J Med 362:361–362

    Article  PubMed  CAS  Google Scholar 

  28. Insel PA (1996) Seminars in medicine of the Beth Israel Hospital, Boston. Adrenergic receptors–evolving concepts and clinical implications. N Engl J Med 334:580–585

    Article  PubMed  CAS  Google Scholar 

  29. Ubeda M, Kemp DM, Habener JF (2004) Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer’s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology 145:3023–3031

    Article  PubMed  CAS  Google Scholar 

  30. Wei FY, Nagashima K, Ohshima T et al (2005) Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med 11:1104–1108

    Article  PubMed  CAS  Google Scholar 

  31. Ubeda M, Rukstalis JM, Habener JF (2006) Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J Biol Chem 281:28858–28864

    Article  PubMed  CAS  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  Google Scholar 

  34. 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

    Article  PubMed  Google Scholar 

  35. 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

    Article  PubMed  Google Scholar 

  36. 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

    Article  PubMed  Google Scholar 

  37. Alberti KGMM, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus, provisional report of a WHO consultation. Diabet Med 15:539–553

    Article  PubMed  CAS  Google Scholar 

  38. Xiao Z, Xiao J, Jiang Y et al (2006) A novel method based on ligase detection reaction for low abundant YIDD mutants detection in hepatitis B virus. Hepatol Res 34:150–155

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  40. Dudbridge F (2003) Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 25:115–121

    Article  PubMed  Google Scholar 

  41. Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: A flexible statistical power analysis program for the social, b ehavioral, and biomedical sciences. Behav Res Methods 39:175–191

    Article  PubMed  Google Scholar 

  42. Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene–gene and gene–environment interactions. Bioinformatics 19:376–382

    Article  PubMed  CAS  Google Scholar 

  43. Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004

    Article  PubMed  CAS  Google Scholar 

  44. Thomas DC, Clayton DG (2004) Betting odds and genetic associations. J Natl Cancer Inst 96:421–423

    Article  PubMed  Google Scholar 

  45. Kass R, Raftery AE (1995) Bayes factors. J Am Stat Assoc 90:773–795

    Article  Google Scholar 

  46. Liu Y, Yu L, Zhang D et al (2008) Positive association between variations in CDKAL1 and type 2 diabetes in Han Chinese individuals. Diabetologia 51:2134–2137

    Article  PubMed  CAS  Google Scholar 

  47. Sullivan PF (2007) Spurious genetic associations. Biol Psychiatry 61:1121–1126

    Article  PubMed  CAS  Google Scholar 

  48. Xu H, Dembski M, Yang Q et al (2003) Dual specificity mitogen-activated protein (MAP) kinase phosphatase-4 plays a potential role in insulin resistance. J Biol Chem 278:30187–30192

    Article  PubMed  CAS  Google Scholar 

  49. Emanuelli B, Eberlé D, Suzuki R, Kahn CR (2008) Overexpression of the dual-specificity phosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance. Proc Natl Acad Sci USA 105:3545–3550

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank all participating individuals in this study. 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. The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. We are grateful to anonymous peer reviewers for their helpful comments and suggestions.

All genotyping experiments were carried out by Shanghai BioWing Applied Biotechnology Company ( http://www.biowing.com.cn)

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Correspondence to Mao Sheng Yang.

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Bao, X.Y., Peng, B. & Yang, M.S. Replication study of novel risk variants in six genes with type 2 diabetes and related quantitative traits in the Han Chinese lean individuals. Mol Biol Rep 39, 2447–2454 (2012). https://doi.org/10.1007/s11033-011-0995-8

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