Prediabetes is a heterogenous metabolic state with various risk for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic whites without diabetes from the UK Biobank (UKBB) to calculate five partitioned polygenetic risk scores (pPRSs) representing various pathways related to T2D. Consensus clustering was performed in participants with prediabetes in HCHS/SOL (n=3,677) and UKBB (n=16,284) separately, based on these pPRSs. Six clusters of individuals with prediabetes with distinctive patterns of pPRSs and corresponding metabolic traits were identified in the HCHS/SOL, five of which were confirmed in the UKBB. Although baseline glycemic traits were similar across clusters, individuals in Cluster 5 and Cluster 6 showed elevated risk of T2D during follow-up compared to Cluster 1 (RR=1.29 [95% CI 1.08-1.53] and1.34 [1.13-1.60], respectively). Inverse associations between a healthy lifestyle score and risk of T2D were observed across different clusters, with a suggestively stronger association observed in Cluster 5 compared to Cluster 1. Among individuals with healthy lifestyle, those in Cluster 5 had a similar risk of T2D compared to those in Cluster 1 (RR=1.03 [0.91-1.18]). This study identified genetic subtypes of prediabetes which differed in risk of progression to T2D and in benefits from healthy lifestyle.

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