Genetic Subtypes of Prediabetes, Healthy Lifestyle, and Risk of Type 2 Diabetes

Abstract

Prediabetes is a heterogenous metabolic state with various risks for development of type 2 diabetes (T2D). In this study, we used genetic data on 7,227 US Hispanic/Latino participants without diabetes from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and 400,149 non-Hispanic White participants 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 an elevated risk of T2D during follow-up compared with cluster 1 (risk ratios [RRs] 1.29 [95% CI 1.08, 1.53] and 1.34 [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 with cluster 1. Among individuals with a healthy lifestyle, those in cluster 5 had a similar risk of T2D compared with those in cluster 1 (RR 1.03 [0.91, 1.18]). This study identified genetic subtypes of prediabetes that differed in risk of progression to T2D and in benefits from a healthy lifestyle.

Figure 1

Patterns of genetic scores and metabolic traits pattern across clusters of prediabetes. A: Patterns of five pPRSs across six clusters of individuals with prediabetes in HCHS/SOL. B: Patterns of five T2D-related metabolic traits across six clusters of individuals with prediabetes in HCHS/SOL. C: Patterns of five pPRSs across five clusters of individuals with prediabetes in UKBB (cluster 3 was not detected in UKBB). Blue dots on five axes in radar plot show the median values of standardized pPRSs or standardized metabolic traits. TG, triglyceride.

Figure 2

Comparison of baseline metabolic traits and glycemic status across clusters of prediabetes. A: Proportion of individuals with only IGT, only IFG, or both across six clusters in HCHS/SOL. B–D: Box plots of fasting glucose, 2-h glucose after OGTT, and HbA_1c at baseline across six clusters in HCHS/SOL. E and F: Box plots of HbA_1c and random glucose at baseline across five clusters in UKBB.

Figure 3

Clusters of prediabetes, incident T2D, and changes in glycemic traits during follow-up. A: Clusters of prediabetes and risk of T2D in HCHS/SOL, UKBB, and the combined studies. In HCHS/SOL, data are RRs and 95% CIs estimated by Poisson regression after adjustment for age, sex, U.S.-born status, Hispanic/Latino background, education, annual income, Alternate Healthy Eating Index 2020, smoking, drinking, physical activity, and eigenvectors derived from GWAS. In UKBB, data are hazard ratios (HRs) and 95% CIs estimated by Cox proportional hazards regression after adjustment for age, sex, education, Townsend deprivation score, diet score, smoking, drinking, physical activity, and eigenvectors derived from GWAS. In the combined analysis, results from HCHS/SOL and UKBB were combined using fixed-effects meta-analysis. B–E: Box plots of changes in fasting glucose, 2-h glucose after OGTT, HOMA-IR, and HOMA-B over 6 years across six clusters of individuals with prediabetes in HCHS/SOL. *P < 0.05.

Figure 4

Association between healthy lifestyle and incident T2D across clusters of prediabetes. A: Association between healthy lifestyle and incident T2D among all individuals with prediabetes and across clusters of prediabetes. In HCHS/SOL, data are RRs and 95% CIs for incident T2D comparing healthy lifestyle (2nd and 3rd tertiles of the lifestyle score) with unhealthy lifestyle (1st tertile of the lifestyle score), estimated by Poisson regression after adjustment for age, sex, U.S.-born status, Hispanic/Latino background, education, annual income. and eigenvectors derived from GWAS. In UKBB, data are hazard ratios (HRs) and 95% CIs for incident T2D comparing healthy lifestyle (2nd and 3rd tertiles of the lifestyle score) with unhealthy lifestyle (1st tertile of the lifestyle score), estimated by Cox proportional hazards regression after adjustment for age, sex, education, Townsend deprivation score, and eigenvectors derived from GWAS. In the combined analysis, results from HCHS/SOL and UKBB were combined using fixed-effects meta-analysis. B: Risk of T2D in cluster 5 compared with the cluster 1 according to lifestyle (healthy lifestyle: 2nd and 3rd tertiles of the lifestyle score; unhealthy lifestyle: 1st tertile of the lifestyle score). In HCHS/SOL, data are RRs and 95% CIs for incident T2D estimated by Poisson regression after adjustment for the covariates mentioned above. In UKBB, data are HRs and 95% CIs for incident T2D estimated by Cox proportional regression after adjustment for the covariates mentioned above. In the combined analysis, results from HCHS/SOL and UKBB were combined using fixed-effects meta-analysis.