An explained variance-based genetic risk score associated with gestational diabetes antecedent and with progression to pre-diabetes and type 2 diabetes: a cohort study

Objective To determine whether an explained-variance genetic risk score (GRS), with 36 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes (T2D), is also associated with gestational diabetes mellitus (GDM), and with the progression to pre-diabetes and T2D among women with prior GDM. Design A cohort study. Setting Clinical investigation unit of Laval University, Quebec, Canada. Population A cohort of 214 women with prior GDM and 82 controls recruited between 2009 and 2012. Methods Associations between the GRS and GDM. Main outcomes measures GDM and prevalence of pre-diabetes and T2D. Results Women with prior GDM had a higher GRS compared with controls (38.6 +/- 3.9, 95% CI 38.1-39.1, versus 37.4 +/- 3.2, 95% CI 36.7-38.1; P < 0.0001). In women with prior GDM, the explained-variance GRS was higher for pre-diabetic women compared with women who remained normoglucotolerant at testing (1.21 +/- 0.18, 95% CI 1.18-1.23, versus 1.17 +/- 0.15, 95% CI 1.13-1.20; P < 0.0001). Similarly, women with T2D had a higher explained-variance GRS compared with women with prior GDM who remained normoglucotolerant (1.20 +/- 0.18, 95% CI 1.14-1.25, versus 1.17 +/- 0.17, 95% CI 1.13-1.20; P < 0.0001). The predictive effects of the explained-variance GRS, age, and body mass index (BMI), or the additive effects of the three variables, were tested for pre-diabetes and T2D. We observed an area under the curve of 0.6269 (95% CI 0.5638-0.6901) for age and BMI, and adding the explained-variance GRS into the model increased the area to 0.6672 (95% CI 0.6064-0.7281) for the prediction of pre-diabetes. Conclusions An explained-variance GRS is associated with both GDM and progression to pre-diabetes and T2D in women with prior GDM.