Association Between Genetic Risk and Development of Type 2 Diabetes in a General Japanese Population: The Hisayama Study

Context: Although recent genetic studies have identified many susceptibility loci associated with type 2 diabetes (T2D), the usefulness of such loci for precision medicine remains uncertain. Objective: This study investigated the impact of genetic risk score (GRS) on the development of T2D in a general Japanese population. Participants: The current study consists of 1465 subjects aged 40 to 79 years without diabetes who underwent a health examination in 2002. Design: The GRS was generated using the literature-based effect size for T2D of 84 susceptibility loci for the Japanese population, and the risk estimates of GRS on the incidence of T2D were computed by using a Cox proportional hazard model in a 10-year follow-up study. The influence of GRS on the predictive ability was estimated with Harrell C statistics, integrated discrimination improvement (IDI), and continuous net reclassification improvement (cNRI). Results: During the 10-year follow-up, 199 subjects experienced T2D. The risk of developing T2D increased significantly with elevating quintiles of GRS (multivariable-adjusted hazard ratio for the fifth vs first quintile, 2.85; 95% CI, 1.83 to 4.44). When incorporating GRS into the multivariable model comprising environmental risk factors, the Harrell C statistics (95% CI) increased from 0.681 (0.645 to 0.717) to 0.707 (0.672 to 0.742) and the predictive ability of T2D was significantly improved (IDI, 0.0376; 95% CI, 0.0284 to 0.0494; cNRI, 0.3565; 95% CI, 0.1278 to 0.5829). GRS was also associated with the risk of T2D independently of environmental risk factors. Conclusions: These findings suggest the usefulness of GRS for identifying a high-risk population together with environmental risk factors in the Japanese population.