1536-P: Moving from T2D Genetic Clusters to Patients Characteristics

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Introduction and Objective: Clinical/phenotypic associations with various partitioned polygenic risk scores (pPRS) have been reported. However, there is limited data on how they aggregate into patient subgroups. Methods: EMR from T2D patients (n=12,136) were analyzed. K-means clustering was conducted based on the pPRS published by Suzuki et al (Nature, 2024) utilizing pPRS normalized scores, yielding 7 T2D patient subgroups, ranging in subject size from 1658 to 1788. Results: Each of the 7 subgroups presented distinct patterns of pPRS contributions, with one different pPRS being particularly prominent in each of the subgroups. The subjects with T2D in subgroup 1 (driven by the beta cell with positive proinsulin cluster) were older and male predominance (p<.002), while patients in subgroup 5 (dominated by the residual glycemic cluster) were younger, leaner, and had lower triglyceride and higher HDL-C levels (p<.0001). Subgroup 3 (driven by the obesity cluster), presented with the highest BMI (p<.0001). Subgroup 7 (led by the metabolomic syndrome cluster), had higher triglyceride and lower HDL-C levels, with the lowest proportion of males (p<.002). Finally, individuals in subgroups 4 and 6 (both driven by the beta cell with negative proinsulin cluster) presented a higher proportion of being treated with injection therapies (mainly insulin) (using the lowest injection subgroup 1, as a reference)( 4: OR 1.28, 95% CI 1.05-1.54; 6: OR 1.29, 95% CI 1.07-1.56). Conclusion: Our study indicates that T2D genetic pPRS differentially aggregate among subgroups of individuals with T2D in Taiwan Asians, supporting that genetic heterogeneity underlies the clinical heterogeneity within T2D. Disclosure W. Sheu: None. C. Lee: None. T. Hsiao: None. Y. Chen: None. J.I. Rotter: None.

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