Background: Women with prior gestational diabetes (GDM) are at exceptionally high risk for type 2 diabetes (T2D). Yet, little is known about genetic determinants for the progression to T2D from GDM. Further, inference from existing data is hindered by small sample size. In a large study based on two independent populations, we examined a genetic risk score (GRS) for T2D in relation to the progression risk.

Methods: This study included white women in the Diabetes and Women’s Health Study, which followed women with GDM from the Nurses’ Health Study II (NHSII, N = 1998) and the Danish National Birth Cohort (DNBC, N = 550). A GRS of T2D was calculated using 59 T2D SNPs (GRS59) from genome-wide association studies in European populations. GRS scores for beta-cell function (GRSBC) and insulin resistance (GRSIR) were derived based on subsets of these SNPs. The relative risks (RRs) of progression to T2D were estimated using log-binomial regression. RRs from the two cohorts were meta-analyzed using fixed effects models.

Results: During the study follow-ups of more than 10 years after the index pregnancy, 416 (20.8%) in NHSII and 155 (28.2%) women in DNBC developed T2D. GRS59 was positively related to the risk of progression to T2D. RRs (95% CI) for increasing quartiles of GRS59 were 1.00, 0.99 (0.79, 1.23), 1.26 (1.03, 1.55), and 1.25 (1.01, 1.53), respectively (p-trend = 0.008). The associations were significantly stronger among lean (pre-pregnant BMI < 25 kg/m2) than overweight or obese women (p-interaction < 0.001). Further, GRSIR, but not GRSBC, was related to the risk of T2D. RRs (95% CI) for increasing quartiles of GRSIR were 1.00, 1.25 (1.02, 1.55), 1.32 (1.07, 1.64), and 1.29 (1.05, 1.58), respectively (p-trend = 0.02). The results were generally consistent across the two cohorts.

Conclusion: In this large prospective study of women with prior GDM, greater GRS of T2D, especially GRS of insulin resistance, was associated with greater risk of progression to T2D.


M. Li: None. M.L. Rahman: None. J. Wu: None. M. Ding: None. J.E. Chavarro: None. Y. Lin: None. S.H. Ley: None. L. Grunnet: None. S. Hinkle: None. A. Thuesen: None. E. Yeung: None. R.E. Gore-Langton: None. S.J. Sherman: None. L. Hjort: None. F.B. Kampmann: None. P. Damm: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Novo Nordisk A/S. F. Tekola-Ayele: None. A. Liu: None. J. Mills: None. A.A. Vaag: Employee; Self; AstraZeneca. S.F. Olsen: None. F. Hu: None. C. Zhang: None.


Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; March of Dimes Birth Defects Foundation; Innovation Fund Denmark; Health Foundation; Heart Foundation; European Union

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