| Autor: |
Billings, Liana K., Jablonski, Kathleen A., Pan, Qing, Florez, Jose C., Franks, Paul W., Goldberg, Ronald B., Hivert, Marie-France, Kahn, Steven E., Knowler, William C., Lee, Christine G., Merino, Jordi, Huerta-Chagoya, Alicia, Mercader, Josep M., Raghavan, Sridharan, Shi, Zhuqing, Srinivasan, Shylaja, Xu, Jianfeng, Udler, Miriam S. |
| Předmět: |
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| Zdroj: |
Diabetes; Aug2024, Vol. 73 Issue 8, p1352-1360, 9p |
| Abstrakt: |
Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD −0.04, P = 9.6 × 10−7, and −8.45 μU/mg, P = 5.6 × 10−6, respectively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD −4.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function. Article Highlights: Process-specific genetic scores (partitioned polygenic scores [pPS]) help explain clinical heterogeneity in type 2 diabetes, but whether they inform differential response to diabetes prevention strategies is unknown. In the Diabetes Prevention Program clinical trial, we examined pPS for associations with longitudinal glycemic measures and type 2 diabetes development. Higher β-cell pPS was associated with reduced baseline and even further reduced 1-year β-cell function despite diabetes prevention interventions. Diabetes prevention interventions may not optimally prevent β-cell function decline in people with genetic susceptibility for β-cell dysfunction, which may contribute to the heterogeneity seen in progression of diabetes development. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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