Global and partitioned polygenic risk scores: associations with pathophysiology and incidence of type 2 diabetes in people with prediabetes

作者：Elsa Vazquez Arreola, William C. Knowler, Robert L. Hanson · 年份：2026 · DOI：10.2337/figshare.32085156.v1 · 研究领域：Genetic Associations and Epidemiology、Adipokines, Inflammation, and Metabolic Diseases、Diabetes, Cardiovascular Risks, and Lipoproteins

<p dir="ltr">Type 2 diabetes partitioned polygenic risk scores (pPRS) are related to their physiological impact on insulin secretion and sensitivity. We investigated associations of two pPRS sets obtained from multi-ancestry cohorts with the relationship between insulin secretion and sensitivity and diabetes incidence in the Diabetes Prevention Program (DPP). We generated 12 and 8 pPRS from soft and hard-clustering approaches, respectively, in 2052 DPP participants randomized to intensive lifestyle intervention, metformin or placebo. Baseline insulin secretion demand and compensation were estimated through the relationship between secretion and sensitivity. Most expected associations of pPRS with insulin secretion and sensitivity were replicated. Some pPRS associated with lower secretion compensation. Global PRS associations with diabetes incidence were stronger than those of any pPRS in both sets. When insulin secretion compensation and demand modified pPRS associations with diabetes incidence, modification occurred only for demand: higher compensation associated with decreased diabetes incidence regardless of pPRS level. A beta-cell dysfunction pPRS interacted with DPP treatments in a way that suggested that these treatments may be less effective in those genetically predisposed to diabetes due to insulin deficiency. Regardless of genetic risk as measured by pPRS, inadequate compensatory insulin secretion contributes to progression to diabetes in people with prediabet...