AimTo explore the genetic effects ofCYP2C8,CYP2C9,CYP2J2, andEPHX2, the key genes involved in epoxyeicosatrienoic acid processing and degradation pathways in gestational diabetes mellitus (GDM) and metabolic traits in Chinese pregnant women.MethodsA total of 2548 unrelated pregnant women were included, of which 938 had GDM and 1610 were considered as controls. Common variants were genotyped using the Infinium Asian Screening Array. Association studies of single nucleotide polymorphisms (SNPs) with GDM and related traits were performed using logistic regression and multivariable linear regression analyses. A genetic risk score (GRS) model based on 12 independent target SNPs associated with GDM was constructed. Logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders including age, pre-pregnancy body mass index, history of polycystic ovarian syndrome, history of GDM, and family history of diabetes, with GRS entered both as a continuous variable and categorized groups. The relationship between GRS and quantitative traits was also evaluated.ResultsThe 12 SNPs inCYP2C8,CYP2C9,CYP2J2, andEPHX2were significantly associated with GDM after adjusting for covariates (allP< 0.05). The GRS generated from these SNPs significantly correlated with GDM. Furthermore, a significant interaction betweenCYP2J2andCYP2C8in GDM (PInteraction= 0.014, ORInteraction= 0.61, 95%CI 0.41–0.90) was observed.ConclusionWe found significant associations between GDM susceptibility and 12 SNPs of the four genes involved in epoxyeicosatrienoic acid processing and degradation pathways in a Chinese population. Subjects with a higher GRS showed higher GDM susceptibility with higher fasting plasma glucose and area under the curve of glucose and poorer β-cell function.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12937-023-00862-9.