Genome-Wide Association Study (GWAS)-Derived Type 2 Diabetes Risk Variants in Gestational Diabetes Mellitus: Evidence From North India

Introduction: Gestational diabetes mellitus (GDM) is hyperglycaemia first identified during pregnancy. Because GDM and type 2 diabetes mellitus (T2DM) share insulin resistance and β-cell dysfunction, T2DM variants may also influence the risk of GDM. This study examined the association of three genome-wide association study (GWAS)-identified T2DM variants, AP3S2 rs2028299 (C>A), ST6GAL1 rs16861329 (C>T), and VPS26A rs1802295 (C>T), with GDM susceptibility in pregnant women from North India. Methods: This observational case-control study was conducted at the tertiary care antenatal clinic of a medical university in Uttar Pradesh, India, and included 69 women with GDM and 69 age- and BMI-matched non-GDM controls. GDM was diagnosed using a one-step 75 g oral glucose tolerance test (OGTT) according to the Diabetes in Pregnancy Study Group India (DIPSI) criteria (DIPSI ≥140 mg/dL). Genotyping of the three variants was performed using polymerase chain reaction followed by Sanger sequencing. Results: Women with GDM had higher triglyceride (p=0.037) and VLDL (p=0.006) levels than controls. A family history of T2DM was significantly associated with GDM (p=0.024). The AP3S2 A allele increased GDM risk 2.26-fold (OR=2.26, 95% CI: 1.27-4.02, p=0.005). The ST6GAL1 CT genotype (OR=2.30, 95% CI: 1.16-4.58, p=0.017) and T allele (OR=1.95, 95% CI: 1.12-3.41, p=0.018) were also associated with increased GDM risk. Conclusion: In this North Indian case-control study, rs2028299 (AP3S2) and rs16861329 (ST6GAL1) were significantly associated with GDM, suggesting potential overlap in genetic susceptibility with T2DM. However, functional studies and larger multi-center cohorts are needed to clarify biological mechanisms and confirm generalizability.