Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome

International Journal of Obesity volume 29, pages 268–274 (2005)Cite this article

Abstract

OBJECTIVE:

Overexpression of the human transcription factor FOXC2 gene (FOXC2) protects against insulin resistance in mice and a common FOXC2 polymorphism (–512C>T) has been suggested to be associated with insulin resistance in humans. Here, we addressed the potential role for FOXC2 as a candidate gene for type 2 diabetes and associated phenotypes.

MATERIALS AND METHODS:

A case–control study was performed in 390 type 2 diabetic patients and 307 control subjects. The number of patients was increased to a total of 768 subjects for further study of phenotypic differences relating to the dysmetabolic syndrome relative to genetic variation. The FOXC2 –512C>T polymorphism was genotyped by a restriction fragment length polymorphism PCR assay.

RESULTS:

FOXC2 –512C>T allele and genotype distribution did not differ between patients with type 2 diabetes and control subjects, but the C/C genotype was associated with increased body mass index (BMI, kg/m2) (Pa=0.03) among type 2 diabetic patients. The FOXC2 –512C>T polymorphism was a significant independent predictor of BMI (P=0.001) in a multiple regression model including age, gender and affection status. We found no significant association with type 2 diabetes-related metabolic parameters but that the C-allele (P=0.01) and C/C and C/T genotypes (P=0.03) were significantly over-represented in type 2 diabetic males with a concomitant diagnosis of dysmetabolic syndrome.

CONCLUSION:

We conclude that FOXC2 is associated with obesity and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES . The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76–80.

    Article  CAS  PubMed  Google Scholar 

  2. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI . Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000; 26: 163–175.

    Article  CAS  PubMed  Google Scholar 

  3. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tmoita M, Froguel P, Kadowaki T . The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941–946.

    Article  CAS  PubMed  Google Scholar 

  4. Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasada K, Yamauchi T, Otabe S, Okada T, Eto K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Nagai R, Taniyama M, Matsubara K, Yoda M, Nakano Y, Kimura S, Tomita M, Kimura S, Ito C, Froguel P, Kadowaki T . Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002; 51: 536–540.

    Article  CAS  PubMed  Google Scholar 

  5. Love-Gregory L, Wasson J, Lin J, Skolnick G, Suarez B, Permutt MA . An E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPARγPro12Ala variant. Diabetologia 2002; 43: 136–137.

    Google Scholar 

  6. Cederberg A, Grönning LM, Ahrén B, Taskén K, Carlsson P, Enerbäck S . FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 2001; 106: 563–573.

    Article  CAS  PubMed  Google Scholar 

  7. Ridderstråle M, Carlsson E, Klannemark M, Cederberg A, Kösters C, Tornqvist H, Storgaard H, Vaag A, Enerbäck S, Groop L . FOXC2 mRNA and a 5′UTR polymorphism of the gene are associated with insulin resistance. Diabetes 2002; 51: 3354–3660.

    Article  Google Scholar 

  8. Kovacs P, Lehn-Stefan A, Stumvoll M, Bogardus C, Baier L . Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians. Diabetes 2003; 52: 1292–1295.

    Article  CAS  PubMed  Google Scholar 

  9. Osawa H, Onuma H, Murakami A, Ochi M, Nishimiya T, Kato K, Shimizu I, Fujii Y, Ohashi J, Makino H . Systematic search for single nucleotide polymorphisms in the FOXC2 gene. The absence of evidence for the association of three frequent single nucleotide polymorphisms and four common haplotypes with Japanese type 2 diabetes. Diabetes 2003; 52: 562–567.

    Article  CAS  PubMed  Google Scholar 

  10. Yanagisawa K, Hingstrup-Larsen L, Andersen G, Drivsholm T, Cederberg A, Westergren R, Borch-Johnsen K, Pedersen O, Enerbäck S, Hansen T . The FOXC2 –512C>T variant is associated with hypertriglyceridaemia and increased serum C-peptide in Danish Caucasian glucose-tolerant subjects. Diabetologia 2003; 46: 1576–1580.

    Article  CAS  PubMed  Google Scholar 

  11. Groop L, Orho-Melander M . The dysmetabolic syndrome. J Intern Med 2001; 250: 105–120.

    Article  CAS  PubMed  Google Scholar 

  12. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L . Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683–689.

    Article  CAS  PubMed  Google Scholar 

  13. Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, Ehrnström BO, Forsén B, Isomaa B, Snickars B, Taskinen MR . Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 1996; 45: 1585–1593.

    Article  CAS  PubMed  Google Scholar 

  14. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . 1985 Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  PubMed  Google Scholar 

  15. World Health Organisation. Report of a WHO Consultation: Definition of Metabolic Syndrome in Definition, Diagnosis, and Classification of Diabetes Mellitus and its Complications. I. Diagnosis and Classification of Diabetes Mellitus. World Health Organisation, Department of Non communicable Disease Surveillance: Geneva; 1999.

  16. Alberti KG, Zimmet PZ . Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetes Med 1998; 15: 539–553.

    Article  CAS  Google Scholar 

  17. Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G, Bester A, Boyd C, Mathew C . Blot hybridisation analysis of genomic DNA. J Med Genet 1984; 21: 164–172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Beck-Nielsen H, Groop LC . Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994; 94: 1714–1721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Carey DG, Nguyen TV, Campbell LV, Chisholm LV, Kelly P . Genetic influences on central abdominal fat: a twin study. Int J Obes Relat Metab Disord 1996; 20: 722–726.

    CAS  PubMed  Google Scholar 

  20. Samaras K, Spector TD, Nguyen TV, Baan K, Campbell LV, Kelly P . Independent genetic factors determine the amount and distribution of fat in women after the menopause. J Clin Endocrinol Metab 1997; 82: 781–785.

    CAS  PubMed  Google Scholar 

  21. Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW . Allelic variation in human gene expression. Science 2002; 297: 1143.

    Article  CAS  PubMed  Google Scholar 

  22. Grönning LM, Cederberg A, Miura N, Enerbäck S, Taskén K . Insulin and TNFα induce expression of the forkhead transcription factor gene Foxc2 in 3T3-L1 adipocytes via PI3-kinase. Mol Endocrinol 2002; 16: 873–883.

    PubMed  Google Scholar 

Download references

Acknowledgements

This investigation was funded by the Crafoord Foundation, Malmö University Hospital Foundation, the Albert Påhlsson Foundation, the Swedish Medical Research Counsil, the Diabetes Association in Malmö, the Juvenile Diabetes-Wallenberg Foundation, the Lundberg Foundation, EC-GIFT, the Novo Nordisk Foundation, Region Skåne, ALF, the Magnus Bergvall Foundation, the Fredrik and Ingrid Thurings Foundation and the Borgströms Foundation. We are greatly indebted to the study subjects for their participation.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Lund University, University Hospital MAS, Malmö, Sweden

    E Carlsson, L Groop & M Ridderstråle

Authors
  1. E Carlsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Groop
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Ridderstråle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Carlsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carlsson, E., Groop, L. & Ridderstråle, M. Role of the FOXC2 –512C>T polymorphism in type 2 diabetes: possible association with the dysmetabolic syndrome. Int J Obes 29, 268–274 (2005). https://doi.org/10.1038/sj.ijo.0802876

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0802876

Keywords

This article is cited by

Search

Advanced search

Quick links