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Abstract

We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q1. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7–like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 × 10−9). This was replicated in a Danish cohort (P = 4.8 × 10−3) and in a US cohort (P = 3.3 × 10−9). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box–containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway2.

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References

  1. 1.

    et al. Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. Am. J. Hum. Genet. 73, 323–335 (2003).

  2. 2.

    , & TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J. Biol. Chem. 280, 1457–1464 (2005).

  3. 3.

    , & Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001).

  4. 4.

    Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes 39, 1315–1319 (1990).

  5. 5.

    et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).

  6. 6.

    et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat. Genet. 26, 163–175 (2000).

  7. 7.

    et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52, 568–572 (2003).

  8. 8.

    et al. Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am. J. Hum. Genet. 64, 1127–1140 (1999).

  9. 9.

    & Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987).

  10. 10.

    The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  11. 11.

    & Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

  12. 12.

    & Allele-sharing models: LOD scores and accurate linkage tests. Am. J. Hum. Genet. 61, 1179–1188 (1997).

  13. 13.

    , & Wnt signaling: physiology and pathology. Growth Factors 22, 141–150 (2004).

  14. 14.

    & New aspects of Wnt signaling pathways in higher vertebrates. Curr. Opin. Genet. Dev. 11, 547–553 (2001).

  15. 15.

    & Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).

  16. 16.

    et al. The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines. Cancer Res. 60, 3872–3879 (2000).

  17. 17.

    , & Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N. Engl. J. Med. 345, 971–980 (2001).

  18. 18.

    , , , & Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432, 1027–1032 (2004).

  19. 19.

    et al. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat. Genet. 32, 245–253 (2002).

  20. 20.

    et al. A polymorphism in the TCF7 gene, C883A, is associated with type 1 diabetes. Diabetes 52, 1579–1582 (2003).

  21. 21.

    & Beta-catenin–a linchpin in colorectal carcinogenesis? Am. J. Pathol. 160, 389–401 (2002).

  22. 22.

    et al. Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 5, 91–102 (2004).

  23. 23.

    et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat. Genet. 19, 379–383 (1998).

  24. 24.

    , , & Does serum cholesterol contribute to vertebral bone loss in postmenopausal women? Bone 32, 8–14 (2003).

  25. 25.

    The interaction of selection and linkage. II. Optimum models. Genetics 50, 757–782 (1964).

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Acknowledgements

We thank the members of the International HapMap Consortium for providing valuable data which were crucial for parts of our analysis.

Author information

Affiliations

  1. deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.

    • Struan F A Grant
    • , Gudmar Thorleifsson
    • , Inga Reynisdottir
    • , Andrei Manolescu
    • , Jesus Sainz
    • , Agnar Helgason
    • , Hreinn Stefansson
    • , Valur Emilsson
    • , Anna Helgadottir
    • , Unnur Styrkarsdottir
    • , Kristinn P Magnusson
    • , G Bragi Walters
    • , Ebba Palsdottir
    • , Thorbjorg Jonsdottir
    • , Thorunn Gudmundsdottir
    • , Arnaldur Gylfason
    • , Jona Saemundsdottir
    • , Unnur Thorsteinsdottir
    • , Jeffrey R Gulcher
    • , Augustine Kong
    •  & Kari Stefansson
  2. Icelandic Heart Association, 201 Kopavogur, Iceland.

    • Rafn Benediktsson
    • , Vilmundur Gudnason
    •  & Gunnar Sigurdsson
  3. National University Hospital, 108 Reykjavik, Iceland.

    • Rafn Benediktsson
    •  & Gunnar Sigurdsson
  4. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 USA.

    • Robert L Wilensky
    • , Muredach P Reilly
    •  & Daniel J Rader
  5. Center for Clinical and Basic Research A/S, 2750 Ballerup, Denmark.

    • Yu Bagger
    •  & Claus Christiansen

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Competing interests

S.F.A.G., G.T., I.R., A.M., J. Sainz, A. Helgason, H.S., V.E., A. Helgadottir, U.S., K.P.M., G.B.W., E.P., T.J., T.G., A.G., J. Saemundsdottir, U.T., J.R.G., A.K. and K.S. own stock or stock options in deCODE Genetics.

Corresponding authors

Correspondence to Struan F A Grant or Kari Stefansson.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    A phylogenetic network representing the genealogical relationships between haplotypes in the TCF7L2 gene.

  2. 2.

    Supplementary Table 1

    Genotype summaries for DG10S478 and the five correlated SNPs for the cohorts from Iceland, Denmark and USA.

  3. 3.

    Supplementary Table 2

    Correlation of five selected public SNPs from the CEPH Utah HapMap with composite allele X of microsatellite DG10S478 in the cohorts from Iceland, Denmark and USA.

  4. 4.

    Supplementary Table 3

    Association of the at-risk alleles of the five selected SNPs and the composite allele X of the microsatellite DG10S478 to type 2 diabetes in Iceland, Denmark and USA.

  5. 5.

    Supplementary Table 4

    Combined association of the at-risk alleles of the five selected SNPs and the composite allele X of microsatellite DG10X478 to type 2 diabetes in all three cohorts.

  6. 6.

    Supplementary Table 5

    Age and BMI ranges for the cohorts from Iceland, Denmark and USA.

  7. 7.

    Supplementary Table 6

    Association between copies of composite allele X of DG10S478 and covariates within affected and control individuals separately.

  8. 8.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ng1732

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