Abstract 16172: Association of Genetic Variation in the α2A-adrenergic Receptor Gene With Risk of Gestational Diabetes

Introduction: Normal pregnancy is characterized by both increased sympathetic activity and an increased in insulin secretion due to insulin resistance. Sympathetic activation suppresses insulin secretion via the pancreatic α2A-adrenergic receptor; gain-of-function variants in its gene ( ADRA2A ) are associated with decreased insulin secretion and increased risk of type 2 diabetes (T2DM). Hypothesis: We hypothesized that because of the increase in sympathetic tone and insulin requirements during pregnancy, effects of ADRA2A genetic variation on glucose homeostasis may be particularly pronounced and would be associated with risk of gestational diabetes (GDM). Methods: We conducted a case-control study using BioVU, a DNA biobank linked to de-identified electronic medical records at Vanderbilt Medical Center. Using bioinformatic algorithms and manual review, we identified 458 cases of GDM and 1537 controls among pregnant women of European ancestry without preexisting diabetes. Cases of GDM had a positive 100g oral glucose tolerance test during pregnancy using Carpenter and Coustan criteria, or a physician’s diagnosis, or an ICD9 billing code for glucose intolerance in pregnancy with an intervention for GDM (nutritional or antidiabetic drug); controls were pregnant women with a normal 50g glucose challenge test. We genotyped 9 ADRA2A SNPs and performed a logistic regression adjusting for maternal age, parity, maternal body mass index (BMI) and a single-count genetic risk score (GRS) that included 33 non-adrenergic SNPs previously associated with T2DM. Results: Two ADRA2A SNPs, rs1800038 (OR=2.47, P=0.014) and rs3750625 (OR=1.56, P=0.010), were associated with increased risk of GDM, and one (rs11195418) with decreased risk (OR=0.62, P=0.024). The associations remained significant after adjustment for age, parity, BMI, and the T2DM GRS (see Figure). Conclusions: ADRA2A genetic variation contributes independently to the risk of GDM in Caucasian women.