Diabetes Genetic Clusters and Clinical Outcomes in the Chronic Renal Insufficiency Cohort

Background Type 2 diabetes (T2D) exhibits biological and pathophysiological heterogeneity, which may contribute to variations in diabetes-related complications, particularly in high-risk populations such as individuals with chronic kidney disease (CKD). Prior research has explored T2D mechanisms using partitioned polygenic scores (PGS), derived from distinct clusters of variants according to their associations with cardiometabolic traits. In this study, we investigated whether cluster-specific partitioned PGS are associated with cardiovascular outcomes and CKD progression in individuals with CKD. Methods We used genome-wide genotype data from the Chronic Renal Insufficiency Cohort (CRIC) to calculate both a total PGS for T2D and partitioned PGS for T2D clusters. We examined their associations with cardiometabolic traits and conducted time-to-event analysis to assess their association with mortality (overall and cardiovascular), incident cardiovascular outcomes (myocardial infarction, stroke, heart failure, atrial fibrillation, peripheral artery disease, and a composite of major cardiovascular events) and CKD progression. Results Among 3,577 CRIC participants (mean age 58 years, 45% were women, 49% had T2D), the total PGS was significantly associated with higher hemoglobin A1C (p=4.8 x 10 -21 ) among nondiabetic participants. Cluster-specific partitioned PGS in CRIC captured distinct cardiometabolic profiles corresponding to T2D mechanistic subtypes, particularly the obesity cluster, the β-cell dysfunction with positive proinsulin cluster, and the lipodystrophy cluster. The obesity cluster partitioned PGS was significantly associated with incident atrial fibrillation (p=2.89 x 10 -4 ) and overall mortality (p= 4.29 x 10 -4 ), but the association with atrial fibrillation was attenuated when accounting for competing risk of death (p=0.002). The β-cell dysfunction with negative proinsulin cluster was inversely associated with CKD progression (p=2.48 x 10 -5 ). Conclusions Our findings suggest that T2D driven by insulin resistance and obesity contributes to a higher risk of overall death in individuals with CKD and explain in part the higher risk of atrial fibrillation. These results highlight the importance of considering T2D heterogeneity when assessing cardiovascular risk in this population.