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Genome-Wide Polygenic Risk Score Predicts Incident Type 2 Diabetes in Women with History of Gestational Diabetes

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posted on 2024-06-28, 14:52 authored by Jaewon Choi, Hyunsuk Lee, Alan Kuang, Alicia Huerta-Chagoya, Denise M. Scholtens, Daeho Choi, Minseok Han, William L. Lowe Jr., Alisa K. Manning, Hak Chul Jang, Kyong Soo Park, Soo Heon Kwak

Objective Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women.

Research Design and Methods Using five independent cohorts representing four different ancestries (N=1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility.

Results Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (-0.08 vs 0.31, P=2.3×10-11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05‒2.21, P=0.03). In a model that includes age, family history of diabetes, systolic blood pressure and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15‒0.49, P=3.0×10-4). Although there was variation, a similar trend was observed across study cohorts.

Conclusion In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D.

Funding

This study was supported by a grant from the National Human Genome Research Institute (U01HG011723), the National Research Foundation of Korea grant funded by the Korean Ministry of Science and ICT (RS-2023-00262002), and by the Ministry of Food and Drug Safety grant (23212MFDS202) in 2023 awarded to S.H.K. H.L. was supported by the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. A.K., D.M.S. and W.L.L. were supported by U01DK094830 from the National Institute of Diabetes and Digestive and Kidney Diseases and R01-HD-34242 and R01-HD-34243 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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