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

Abstract

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. 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 AE 3.9, 95% CI 38.1-39.1, versus 37.4 AE 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 AE 0.18, 95% CI 1.18-1.23, versus 1.17 AE 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 AE 0.18, 95% CI 1.14-1.25, versus 1.17 AE 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.

Genetic factors and risk of type 2 diabetes among women with a history of gestational diabetes: findings from two independent populations

“…Although women with a history of GDM have a greatly increased risk for T2D, not all develop T2D. Few studies have examined genetic factors of T2D in this high-risk population 10–13. A higher GRS for T2D was significantly associated with a higher risk of T2D in several studies of women with a history of GDM 10–12.…”

“…Few studies have examined genetic factors of T2D in this high-risk population 10–13. A higher GRS for T2D was significantly associated with a higher risk of T2D in several studies of women with a history of GDM 10–12. However, inferences from these studies are hindered by small numbers of T2D cases (n<150), and relatively short follow-up periods (<5 years).…”

“…Lastly, the long study follow-up, an average of 21 years in the NHSII and 13 years in DNBC, presumably allowed us to capture a larger proportion of women who would eventually develop T2D. In comparison, existing studies either had less than 5 years of follow-up after the GDM pregnancy10–12 or missed T2D cases which occurred within the first decade after the GDM pregnancy 13…”

“…However, as women with a history of GDM already have an elevated baseline genetic risk for T2D compared with the general population,8 9 the role genetic factors play in the development of T2D among women with a history of GDM may differ from that in the general population. So far, few studies have examined the association of genetic factors including individual SNPs and GRSs with the risk of T2D among women with a history of GDM10–13; inferences from these studies are hindered by small numbers of T2D cases (n<150), and relatively short follow-up periods (<5 years). Lastly, no study has examined how non-genetic factors may modify the genetic risk for T2D among women with a history of GDM, although such knowledge may guide targeted T2D prevention among this high-risk population.…”

Common Type 2 Diabetes Genetic Risk Variants Improve the Prediction of Gestational Diabetes

“…The AUC of the ROC curve when considering genetic polymorphisms, BMI and age was significantly greater than the AUC of the ROC curve for age and BMI alone. The authors suggested that using genetic polymorphisms in combination with traditional risk factors for type 2 diabetes was likely to be more accurate for predicting the future risk of progression to type 2 diabetes in women with prior GDM [21].…”