title: Metabolite traits and genetic risk provide complementary information for the prediction of future type 2 diabetes.
abstract: OBJECTIVE
  A genetic risk score (GRS) comprised of single nucleotide polymorphisms (SNPs) and metabolite biomarkers have each been shown, separately, to predict incident type 2 diabetes. We tested whether genetic and metabolite markers provide complementary information for type 2 diabetes prediction and, together, improve the accuracy of prediction models containing clinical traits.
  
  
  METHODS
  Diabetes risk was modeled with a 62-SNP GRS, nine metabolites, and clinical traits. We fit age- and sex-adjusted logistic regression models to test the association of these sources of information, separately and jointly, with incident type 2 diabetes among 1,622 initially nondiabetic participants from the Framingham Offspring Study. The predictive capacity of each model was assessed by area under the curve (AUC).
  
  
  RESULTS
  Two hundred and six new diabetes cases were observed during 13.5 years of follow-up. The AUC was greater for the model containing the GRS and metabolite measurements together versus GRS or metabolites alone (0.820 vs. 0.641, P < 0.0001, or 0.820 vs. 0.803, P = 0.01, respectively). Odds ratios for association of GRS or metabolites with type 2 diabetes were not attenuated in the combined model. The AUC was greater for the model containing the GRS, metabolites, and clinical traits versus clinical traits only (0.880 vs. 0.856, P = 0.002).
  
  
  CONCLUSIONS
  Metabolite and genetic traits provide complementary information to each other for the prediction of future type 2 diabetes. These novel markers of diabetes risk modestly improve the predictive accuracy of incident type 2 diabetes based only on traditional clinical risk factors.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Diabetes Unit, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA gwalford@partners.org jcflorez@partners.org.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Walford
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, MA.
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Porneala
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA General Medicine Division, Massachusetts General Hospital, Boston, MA Division of Endocrinology and Metabolic Diseases, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Dauriz
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA Section of General Internal Medicine, VA Boston Healthcare System, Boston, MA Division of General Medicine and Primary Care, Brigham and Women's Hospital, Boston, MA.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Vassy
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA Cardiovascular Division, Brigham and Women's Hospital, Boston, MA.
authors.forename: Susan
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA Renal Division, Massachusetts General Hospital, Boston, MA.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.affiliation: Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA General Medicine Division, Massachusetts General Hospital, Boston, MA Framingham Heart Study of the National Heart, Lung, and Blood Institute, Framingham, MA.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA Cardiology Division, Massachusetts General Hospital, Boston, MA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Diabetes Unit, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA gwalford@partners.org jcflorez@partners.org.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D019540:Area Under Curve; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors