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Previous Volume 359:2220-2232 November 20, 2008 Number 21 Next

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ABSTRACT

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=1.0x10^–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.

Source Information

From the Department of Clinical Sciences, Lund University, Malmö, Sweden (V.L., A.J., P.A., G.B., P.N., L.G.); the University of Pisa, Pisa, Italy (N.P.); the Folkhalsan Research Center (B.I., T.T.) and Helsinki University Central Hospital and the University of Helsinki (T.T., L.G.) — all in Helsinki, Finland; and the Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, and Massachusetts General Hospital, Boston (D.A.).

Address reprint requests to Dr. Lyssenko at the Department of Clinical Sciences, Diabetes, and Endocrinology, Lund University, CRC, Malmö University Hospital, 20502 Malmö, Sweden, or at valeri.lyssenko{at}med.lu.se.

Full Text of this Article

Related Letters:

Clinical Risk Factors, DNA Variants, and the Development of Type 2 Diabetes
Narayan K.M. V., Weber M. B., Gulcher J., Stefansson K., Lyssenko V., Nilsson P., Groop L.
Extract | Full Text | PDF  
N Engl J Med 2009; 360:1360-1361, Mar 26, 2009. Correspondence

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