Associations of ASIC2, IKZF3, and GSDMB Variants with Gestational Diabetes Mellitus and Their Interactions with Environmental Exposures Among Chinese Women

Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and offspring cardiometabolic outcomes. However, the combined effects of genetic susceptibility and environmental exposures on GDM risk remain unclear. We conducted a case–control study of 1564 pregnant women in China. Targeted next-generation sequencing was used to genotype ASIC2/rs12450465, IKZF3/rs2060941, and GSDMB/rs2305479. Associations of individual variants and haplotypes with GDM were evaluated, and interactions with exposure to PM2.5, O3, and monoisobutyl phthalate (MIBP) were assessed. Multiple comparisons in the primary covariate-unadjusted analyses were controlled using the Benjamini–Hochberg false discovery rate (FDR) procedure. In the overall study population, the rs12450465-rs2060941-rs2305479 T-T-T haplotype was significantly associated with GDM after FDR correction (nominal p = 0.00266, FDR-adjusted p = 0.0133, OR = 1.741, 95% CI = 1.208–2.509). Several gene–gene and gene–air pollutant interaction signals, particularly those involving O3 exposure, remained statistically significant after FDR correction in the primary covariate-unadjusted analyses. Among 289 participants with urinary MIBP measurements, the T-T-T haplotype was similarly associated with GDM (nominal p = 0.003837, FDR-adjusted p = 0.0192, OR = 2.980, 95% CI = 1.378–6.446), and additional interaction signals between this haplotype and MIBP exposure were identified. These findings suggest that gene–environment interactions may contribute to susceptibility to GDM and identify the T-T-T haplotype as a potential susceptibility marker. Nevertheless, the results, particularly those from the smaller MIBP subgroup and the covariate-unadjusted interaction analyses, require validation in larger, independent, and more diverse populations.