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Diabetes. 2015 May;64(5):1830-40. doi: 10.2337/db14-1504. Epub 2014 Dec 4.

Sixty-five common genetic variants and prediction of type 2 diabetes.

Author information

  • 1Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K. p.talmud@ucl.ac.uk.
  • 2Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K.
  • 3Department of Primary Care and Population Health, University College London, Royal Free Campus, London, U.K.
  • 4Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, U.K.
  • 5Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K.
  • 6University College London Genetics Institute, Department of Genetics, Environment and Evolution, London, U.K.
  • 7Centre for Population Health Sciences, University of Edinburgh, Edinburgh, U.K.
  • 8Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K.
  • 9Medical Research Council Unit for Lifelong Health and Ageing at University College London, London, U.K. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
  • 10School of Social and Community Medicine, University of Bristol, Bristol, U.K. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
  • 11Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K. Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 12Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
  • 13Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K. Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
  • 14Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
  • 15Metabolic Unit, Western General Hospital, Edinburgh, U.K.
  • 16Genetics Division, Research and Development, GlaxoSmithKline, Harlow, U.K.
  • 17Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, U.K. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, U.K.
  • 18Department of Epidemiology and Public Health, University College London Institute of Epidemiology and Health Care, University College London, London, U.K. Centre for Clinical Pharmacology, University College London, London, U.K.

Abstract

We developed a 65 type 2 diabetes (T2D) variant-weighted gene score to examine the impact on T2D risk assessment in a U.K.-based consortium of prospective studies, with subjects initially free from T2D (N = 13,294; 37.3% women; mean age 58.5 [38-99] years). We compared the performance of the gene score with the phenotypically derived Framingham Offspring Study T2D risk model and then the two in combination. Over the median 10 years of follow-up, 804 participants developed T2D. The odds ratio for T2D (top vs. bottom quintiles of gene score) was 2.70 (95% CI 2.12-3.43). With a 10% false-positive rate, the genetic score alone detected 19.9% incident cases, the Framingham risk model 30.7%, and together 37.3%. The respective area under the receiver operator characteristic curves were 0.60 (95% CI 0.58-0.62), 0.75 (95% CI 0.73 to 0.77), and 0.76 (95% CI 0.75 to 0.78). The combined risk score net reclassification improvement (NRI) was 8.1% (5.0 to 11.2; P = 3.31 × 10(-7)). While BMI stratification into tertiles influenced the NRI (BMI ≤24.5 kg/m(2), 27.6% [95% CI 17.7-37.5], P = 4.82 × 10(-8); 24.5-27.5 kg/m(2), 11.6% [95% CI 5.8-17.4], P = 9.88 × 10(-5); >27.5 kg/m(2), 2.6% [95% CI -1.4 to 6.6], P = 0.20), age categories did not. The addition of the gene score to a phenotypic risk model leads to a potentially clinically important improvement in discrimination of incident T2D.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

PMID:
25475436
[PubMed - indexed for MEDLINE]
PMCID:
PMC4407866
Free PMC Article
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