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Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women

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Abstract

Common variants of TCF7L2, encoding a β-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C > T) and rs12255372 (IVS4G > T)] which showed strong linkage disequilibrium (D′ = 0.88, p < 0.001; R 2 = 0.76, p < 0.001). The IVS5T allele frequency was 0.28 (95% CI 0.27–0.29) and 0.33 (0.28–0.39) in healthy and T2D, respectively (p = 0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13–2.41) and 1.87 (0.99–3.53), respectively, p < 0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34–0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24–1.65) and 2.11 (1.69–2.63), respectively p = <0.0001. A similar effect was observed in 919 T2D Indian Asians [OR = 1.50 (1.14–1.99) and 1.64 (1.03–2.63) p = 0.003] and 385 Afro-Caribbean subjects [OR = 1.25 (0.90–1.75) and 1.32 (0.74–2.33) p = 0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G > T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D′ = 0.94), but much weaker in Afro-Caribbeans (D′ = 0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.

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Acknowledgements

We thank our clinical colleague Dr. Hugh Mathur for supporting the recruitment of the EDSC patients, and the following general practices who collaborated in the study: The Surgery, Aston Clinton, Upper Gordon Road, Camberley; The Health Centre, Carnoustie; Whittington Moor Surgery, Chesterfield; The Market Place Surgery, Halesworth; The Health Centre, Harefield; Potterells Medical Centre, North Mymms; Rosemary Medical Centre, Parkstone, Poole; The Health Centre, St. Andrews. NPHSII was supported by the UK Medical Research Council, the US National Institutes of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. EDSC was supported by the Coronary Thrombosis Trust. JWS was supported by a clinical training fellowship from Diabetes UK (BDA: RD01/0001357). DRG and JAC and SEH are supported by the British Heart Foundation (FS/04/012:RG2005/014). This work was carried out in part with support from the Department of Health and the Department of Trade and Industry for the IDEAS Genetics Knowledge Park. A list of the WHSS Group is given elsewhere [10]. The study has received support from the former Wandsworth and South Thames Regional Health Authorities, NHS R&D Directorate, British Heart Foundation, former British Diabetic Association and The Stroke Association. Financial support for the PREDICT Study was provided by the British Heart Foundation and the Tompkins Foundation. IFG is supported by the Heart Disease and Diabetes Research Trust. Financial contributions were also received from AstraZeneca UK, Fournier Phamaceuticals, and TakedaUK. The contribution of other members of the PREDICT Study group [13] is gratefully acknowledged including A. Dunlop and A. Widdowson.

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Authors and Affiliations

  1. Department of Medicine, Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University Street, London, WC1E 6JF, UK

    Steve E. Humphries, David Gable, Jackie A. Cooper, Helen Ireland, Ka Wah Li, Jutta Palmen & Philippa J. Talmud

  2. Diabetes Research Group, The Medical School, University of Wales Swansea, Singleton, Park, Swansea, SA2 8PP, UK

    Jeffrey W. Stephens

  3. Department of Diabetes and Endocrinology, UCL Hospitals, Mortimer Street, London, W1T 3AA, UK

    Steven J. Hurel

  4. Clinical Sciences Research Institute, UHCW Campus, Warwick Medical School, Clifford Bridge Road, Coventry, CV2 2DX, UK

    Michelle A. Miller & Francesco P. Cappuccio

  5. Endocrinology and Metabolic Medicine, Imperial College London and St Mary’s Hospital, London, UK

    Robert Elkeles & Ian Godsland

  6. Medical Research Council Cardiovascular Group, Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, EC1M 6BQ, UK

    George J. Miller

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  1. Steve E. Humphries
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  2. David Gable
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  3. Jackie A. Cooper
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  9. Michelle A. Miller
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  10. Francesco P. Cappuccio
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  11. Robert Elkeles
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  12. Ian Godsland
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  13. George J. Miller
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  14. Philippa J. Talmud
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Correspondence to Steve E. Humphries.

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Humphries, S.E., Gable, D., Cooper, J.A. et al. Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. J Mol Med 84, 1005–1014 (2006). https://doi.org/10.1007/s00109-006-0108-7

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