SAT-123 Burden of Type 2 Diabetes Genetic Risk Alleles Differs Among Physiologic Subtypes of Gestational Diabetes Mellitus

Background: Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse perinatal outcomes and future maternal type 2 diabetes (T2D). We previously demonstrated that women with GDM can be classified into subtypes according to the predominant late pregnancy physiologic defect leading to hyperglycemia (i.e. predominant insulin secretion or sensitivity defect, defined using oral glucose tolerance test-based indices); the risk of adverse perinatal outcomes differs among subtypes. In the present analysis, we tested whether women with different GDM subtypes carry different burdens of genetic risk alleles known to be associated with T2D and related glycemic traits. Methods: We built genetic risk scores (GRSs) using variant alleles known to be associated with T2D and glycemic traits in non-pregnant Europeans (T2D: 85 variants, fasting glucose: 38, fasting insulin: 18, reduced insulin secretion: 24, reduced insulin sensitivity: 14). In the Genetics of Glucose Regulation in Gestation and Growth cohort, we compared these GRSs among previously defined GDM subtypes and pregnant women with normal glucose tolerance (NGT) using the Kruskal-Wallis test. We performed post-hoc comparisons using Dunn’s test with Bonferroni-adjusted P-values. Results: Of 550 women, 43 (7.8%) developed GDM. Of women with GDM, 23 (53%) had a predominant insulin sensitivity defect, 13 (30%) had a predominant insulin secretion defect, and 6 (14%) had mixed defects. The insulin secretion and T2D GRSs were associated with GDM (insulin secretion: unadjusted odds ratio [95% confidence interval] 1.12 [1.02, 1.24]; T2D: 1.06 [1.01, 1.11]); the other GRSs showed consistent trends toward association (fasting glucose: 1.07 [1.00, 1.15], P=0.06; fasting insulin: 1.09 [0.97, 1.23], P=0.10; insulin sensitivity: 1.14 [0.99, 1.32], P=0.08). The fasting insulin, T2D, and insulin secretion GRSs differed by GDM subtype. Compared to women with NGT, women with GDM due to an insulin sensitivity defect had higher mean [SD] fasting insulin GRS (21.5[2.0] vs 20.2[2.7], P=0.01) and similar T2D GRS (95.0 [7.9] vs. 95.0[6.1], P>0.99). Women with GDM due to an insulin secretion defect had higher mean T2D GRS (99.6[6.1] P=0.04 vs. NGT) and a trend toward higher mean insulin secretion GRS (24.1[2.0] vs 22.4[3.1] in NGT, P=0.10). Women with mixed defects had higher mean T2D GRS (104.6[7.4], P=0.01) and insulin secretion GRS (27.4[4.1], P=0.01), compared to women with NGT. Discussion: Physiologic subtypes of GDM differ genetically. Women with GDM due to a predominant insulin secretion defect or a mixed secretion-sensitivity defect carry an increased burden of T2D-associated genetic risk alleles, while women with GDM due to a predominant insulin sensitivity defect do not. Future research should test whether certain physiologic subtypes of GDM have an increased risk of progression to T2D.