Polygenic Assessment and Testing of Heterogeneity and Subtypes in Type 2 Diabetes
This study examines whether genetically defined subtypes of type 2 diabetes correspond to differences in physiology and treatment response, using a recall-by-genotype design to recruit participants across distinct genetic risk pathways.
Aims & What Participation Involves
Aims
- Identify adults with high genetic risk for type 2 diabetes across distinct pathophysiological pathways.
- Characterize differences in glucose, insulin, and hormonal responses by genetic risk group.
What Participation Involves
- A baseline visit with a mixed-meal tolerance test to measure glucose, insulin, and hormone levels.
- For eligible participants: an at-home course of a study medication, followed by a second visit with a repeat test.
The genetics behind who PATHS-T2D recruits.
Type 2 diabetes is a multifactorial disease with substantial genetic risk, but the underlying biological mechanisms are not fully understood. This study identified multi-ancestry type 2 diabetes genetic clusters by analyzing genetic data from diverse populations across 37 published genome-wide association studies representing more than 1.4 million individuals.
Twelve genetic clusters were identified with distinct cardiometabolic trait associations, including two lipodystrophy-related clusters, and were enriched for specific single-cell regulatory regions. Genetic risk profiles differed in distribution across ancestry groups, offering preliminary insight into ancestry-associated differences in diabetes risk.
These pathway-specific genetic clusters — grouping variants by their relationship to glycemia, insulin, adiposity, and lipid traits — are the same partitioned polygenic scores PATHS-T2D uses to recruit participants across distinct disease mechanisms.