Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study.
OBJECTIVE
Prediction of type 2 diabetes based on genetic testing might improve identification of high-risk subjects. Genome-wide association (GWA) studies identified multiple new genetic variants that associate with type 2 diabetes. The predictive value of genetic testing for prediction of type 2 diabetes in the general population is unclear.


METHODS
We investigated 18 polymorphisms from recent GWA studies on type 2 diabetes in the Rotterdam Study, a prospective, population-based study among homogeneous Caucasian individuals of 55 years and older (genotyped subjects, n = 6,544; prevalent cases, n = 686; incident cases during follow-up, n = 601; mean follow-up 10.6 years). The predictive value of these polymorphisms was examined alone and in addition to clinical characteristics using logistic and Cox regression analyses. The discriminative accuracy of the prediction models was assessed by the area under the receiver operating characteristic curves (AUCs).


RESULTS
Of the 18 polymorphisms, the ADAMTS9, CDKAL1, CDKN2A/B-rs1412829, FTO, IGF2BP2, JAZF1, SLC30A8, TCF7L2, and WFS1 variants were associated with type 2 diabetes risk in our population. The AUC was 0.60 (95% CI 0.57-0.63) for prediction based on the genetic polymorphisms; 0.66 (0.63-0.68) for age, sex, and BMI; and 0.68 (0.66-0.71) for the genetic polymorphisms and clinical characteristics combined.


CONCLUSIONS
We showed that 9 of 18 well-established genetic risk variants were associated with type 2 diabetes in a population-based study. Combining genetic variants has low predictive value for future type 2 diabetes at a population-based level. The genetic polymorphisms only marginally improved the prediction of type 2 diabetes beyond clinical characteristics.
van Hoek
Mandy
M
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
Dehghan
Abbas
A
Witteman
Jacqueline C M
JC
van Duijn
Cornelia M
CM
Uitterlinden
André G
AG
Oostra
Ben A
BA
Hofman
Albert
A
Sijbrands
Eric J G
EJ
Janssens
A Cecile J W
AC
D051722:ADAM Proteins / Q000235:genetics; D000071119:ADAMTS9 Protein; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D027682:Cation Transport Proteins / Q000235:genetics; D056970:Co-Repressor Proteins; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D012307:Risk Factors; D051820:TCF Transcription Factors / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D044465:White People / Q000235:genetics; D000075703:Zinc Transporter 8; D012359:tRNA Methyltransferases
C493966:CDKN2B protein, human; D027682:Cation Transport Proteins; D056970:Co-Repressor Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C498779:IGF2BP2 protein, human; C430460:JAZF1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; C492522:SLC30A8 protein, human; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D000075703:Zinc Transporter 8; C114987:wolframin protein; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human