Abstract MP085: Genotype Predicts Type 2 Diabetes in Adulthood in a Biracial Adolescent Population

Abstract

Background Prediction of type 2 diabetes (T2D) early in the life course, before metabolic derangements occur, might facilitate prevention. In middle-aged adults, genotype risk scores (GRS) predict incident T2D but do not outperform prediction models consisting of clinical variables such as family history, body-mass index (BMI), and routine laboratory tests. Unlike clinical predictors and even family history, however, genotype does not change over the life course. We hypothesized that a diabetes GRS predicts incident adult T2D from adolescence and that the addition of this GRS improves T2D prediction models based on clinical adolescent risk factors alone. Methods The biracial Bogalusa Heart Study is a geographically based cohort study of children aged 4 to 18 years followed serially into adulthood. We limited the present analyses to participants seen in adolescence and followed into adulthood for whom genotype information was available. The baseline examination was the first assessment for each participant after age 12 years. Participants with childhood or type 1 diabetes were excluded. Incident T2D was defined as a fasting glucose ≥126 mg/dL or diabetes treatment after age 19 years. We used Cox regression to build nested T2D prediction models based on clinical risk factors assessed in adolescence (parental history of diabetes, BMI z -score, mean arterial pressure, fasting glucose, HDL cholesterol, and triglycerides) with and without a 38-variant GRS. We used likelihood ratios tests (LRT), differences in C statistics (ΔC), and net reclassification improvement indices (NRI) to assess whether GRS improved prediction in each model. Results Mean age at baseline was 14.4 years (range 12 to 19). Of the 1056 participants, 585 (55%) were girls, and 340 (32%) were black. Ninety (8.5%) developed T2D over a mean 26.3 years of follow-up. GRS significantly predicted incident T2D in all models, with hazard ratios of 1.09 per risk allele (95% CI 1.03, 1.15) in the basic demographic model and 1.06 (95% CI 1.00, 1.13) in the full model. The addition of GRS to all models improved model fit (all LRT p <0.05) but not discrimination (all ΔC p >0.05). The addition of GRS to the demographic model significantly improved the risk classification of the cohort (NRI 24.8%, 95% CI 8.3, 41.7%), but this reclassification was not significant when GRS was added to the full model (NRI 3.9%, 95% CI -5.0, 13.9%). Moreover, the GRS did not meaningfully improve prediction in a model which included only demographics and parental history of diabetes (NRI 0.8%, 95% CI -13.0, 16.0%). We found no interaction between race and GRS in any model (all p >0.05). Conclusions Knowledge of genotype predicts adult T2D in white and black adolescents. Genotype does not meaningfully improve prediction over routinely collected clinical risk factors, including parental history.