4.8 Article

Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes.

Journal

NEW ENGLAND JOURNAL OF MEDICINE
Volume 359, Issue 21, Pages 2220-2232

Publisher

MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0801869

Keywords

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Funding

  1. Swedish Research Council
  2. Linne [31475113580]
  3. Heart and Lung Foundation
  4. Swedish Diabetes Research Society
  5. Nordic Center of Excellence Grant in Disease Genetics
  6. Diabetes Program at the Lund University
  7. Finnish Diabetes Research Society
  8. Sigrid Juselius Foundation
  9. Pahlsson Foundation
  10. Crafoord Foundation
  11. Folkhalsan Research Foundation
  12. Novo Nordisk Foundation
  13. European Network of Genomic and Genetic Epidemiology
  14. Wallenberg Foundation
  15. European Foundation for the Study of Diabetes
  16. Tethys
  17. Merck
  18. Eisai
  19. MPM Capital
  20. Novartis
  21. Bristol-Myers Squibb Foundation
  22. Eli Lilly
  23. GlaxoSmithKline
  24. Aventis
  25. Sanofi

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Background: Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. Methods: We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. Results: Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0 x 10(-4)). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. Conclusions: As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.

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