Prediabetes is a heterogenous metabolic condition. We calculated 5 pathway-based partitioned polygenetic risk scores (pPRS: beta-cell, proinsulin, obesity, lipodystrophy and liver/lipid scores) based on 94 type 2 diabetes (T2D) -associated variants in 3677 individuals with prediabetes from the Hispanic Community Health Study/Study of Latinos. Based on these 5 pPRS, we identified 6 subtypes of prediabetes (n=488∼742 in each cluster) with different pPRS patterns by consensus clustering (Fig 1A) . Phenotypic patterns were consistent with pPRS patterns in these subtypes (Fig 1B; e.g., Cluster 1 had much lower beta-cell score, higher obesity and liver/lipid scores, and higher HOMA-B, BMI and HOMA-IR compared to other clusters) . These subtypes had similar levels of fasting glucose, HbA1c and 2h glucose at baseline but different risk of incident T2D over 6 years (Fig 1C) . Individuals in Cluster 6 featured with a very low proinsulin score had the highest risk of T2D (RR=1.42 [95% CI 1.13, 1.80] compared to Cluster 1) . We examined the association between a lifestyle score, using BMI, alcohol intake, smoking, physical activity and diet, and risk of T2D across 6 subtypes and found significant associations only in Cluster 1 (RR=0.76 [0.62, 0.93]) and Cluster 5 (RR=0.79 [0.67, 0.92]) . In US Hispanics, we identified 6 genetic subtypes of prediabetes which may differ in the development of T2D and benefits from healthy lifestyle.


Y.Li: None. T.Wang: None. J.D.Kaufman: None. R.Kaplan: None. Q.Qi: None. G.Chen: None. J.Moon: None. D.Sotres-alvarez: None. M.L.Daviglus: None. A.Pirzada: n/a. J.Mattei: None. K.M.Perreira: None. S.Wasserthei-smoller: None.

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