SUN-530 Genetic Risk Score as a Predictor of Gestational Diabetes Mellitus: Association with β-Cell Dysfunction and Insulin Resistance

Abstract Disclosure: J. Hryniewicka: None. A. Buczynska: None. A. Krętowski: None. M. Szelachowska: None. Gestational diabetes mellitus (GDM) is affecting 14% of pregnancies worldwide and exposing millions of neonates to maternal hyperglycemia and insulin resistance. This condition increases maternal risk of preeclampsia and type 2 diabetes while predisposing the fetus to macrosomia, neonatal hypoglycemia, and long-term metabolic disorders. Recent genetic studies highlight the role of single nucleotide polymorphisms (SNPs) evaluation offering new insights into GDM pathogenesis and potential targeted interventions. Moreover, the Genetic Risk Score (GRS), calculated as the sum of all risk alleles, may became a novel marker of GDM development. This study aims to investigate whether genetic predisposition of GDM, assessed through GRS, is associated with disturbed glucose metabolism assessed during the oral glucose tolerance test (OGTT) and clinical equations used to evaluate insulin resistance (IR). In this study, we investigated the association between 74 genetic variants across 37 genes involved in glucose metabolism, insulin resistance, obesity and β-cell function with the risk of GDM. A total of 476 pregnant women between 22 and 32 weeks of gestation were enrolled, including 104 diagnosed with GDM and 372 comprising the normoglycemic control group (NGT). Moreover, IR was evaluated using HOMA, HOMA beta, Mastuda index, DI30, DI120, ΔAUCglc/ins30 and ΔAUCglc/ins120. In this study, the GDM group was characterized by higher glucose levels at all time points of the OGTT, as well as higher fasting insulin and insulin levels at 120 minutes since OGTT (all, p<0.001). In the recessive model, GDM were associated with rs2260000 of BAT2 (OR 2.07 [1.06-4.08]), rs10838738 of MTCH2 (OR 1.97 [1.00-3.88]), and rs11605924 of CRY2 (OR 1.76 [1.08-2.86]). Additionally, rs7901695 and rs4506565 of TCF7L2, rs13266634 and rs11558471 of SLC30A8, and rs10946398 of CDKAL1 were found to be associated with GDM in both the allelic and dominant models. Thus, a significant increase in GDM risk was observed following higher GRS values (OR 1.128 [1.070-1.192]). Moreover, a positive correlation was detected between GRS and glucose concentration during OGTT, whereas negative correlations were noted between GRS and indices of β-cell function, including DI30, DI120, the Matsuda index, and insulin levels at 30 minutes of OGTT. GRS demonstrated moderate predictive ability for GDM (AUC = 0.67, p<0.00001), suggesting its clinical relevance in risk assessment. GRS emerged as a novel predictor of GDM risk, with a higher OR than traditional phenotypic risk factors, such as pre-pregnancy BMI. Additionally, the observed correlations between GRS, glucose levels, and insulin secretion indices suggest a genetic influence on β-cell dysfunction and insulin resistance in GDM. Our findings indicate that specific genetic variants evaluated in this study contribute to an increased risk of GDM. Presentation: Sunday, July 13, 2025