Putting Phenotypes and Polygenics into Practice for Diabetes Care (4PDC)

About This Grant

PROJECT SUMMARY Type 2 diabetes (T2D) is a heterogeneous disease with varied clinical characteristics, treatment responses, and complication risks. However, gaps persist in understanding the biological drivers and clinical implications of T2D heterogeneity, limiting the potential to develop personalized and effective approaches to prevention and treatment. Notably, most existing phenotypic classification schemes are based on variables rarely collected in usual care and have derived T2D phenotypes using variables collected only at diabetes onset, greatly limiting practical application. Furthermore, the utilization of genomic data, such as polygenic risk scores (PRS) for T2D phenotypes and complications, offers a unique opportunity to understand the biological mechanisms driving heterogeneous clinical presentations and outcomes of T2D. However, despite the potential of PRS, significant gaps remain. Most studies examining the link between PRS and T2D complications have been studied in European populations, limiting the generalizability of findings to the broader population. Additionally, many existing studies have focused on single time-point measurements, failing to capture the dynamic nature of T2D phenotypes and their progression over time. To overcome these gaps, we will leverage the extensive and nationally representative Kaiser Permanente Research Bank (KPRB) cohort to address T2D heterogeneity in phenotypic presentation and risk of complications through a comprehensive and innovative approach. We aim to identify novel T2D phenotypes using widely available clinical variables from 110,434 individuals across eight U.S. states. By employing advanced data-driven clustering techniques and longitudinal assessment over a mean follow-up of 13 years, we will explore the dynamics of T2D phenotypes over time and with aging, as well as their association with T2D complications. Our study will also integrate polygenic risk scores (PRS) to enhance the precision of phenotype classification and complication prediction, offering insights into the genetic mechanisms underlying T2D heterogeneity. Our aims are to (Aim 1) identify T2D phenotypes and investigate the dynamics of phenotypic allocation with aging amongst members (n=110,434 T2D) of a large nationally representative healthcare delivery system using widely available clinical variables; (Aim 2) examine associations between T2D phenotypes and T2D complications; and (Aim 3) investigate molecular pathways associated with T2D phenotypes and complications. This project will accelerate the progress of translational precision medicine, improve understanding of the pathophysiology of T2D phenotypes, and investigate molecular pathways associated with T2D phenotypes and complications across race, ethnicity, sex, and age groups. This work can inform the development of practical and targeted therapies for improved T2D management and care.