Genetic variants in epoxyeicosatrienoic acid processing and degradation pathways are associated with gestational diabetes mellitus

Abstract

Aim To explore the genetic effects of CYP2C8, CYP2C9, CYP2J2, and EPHX2, the key genes involved in epoxyeicosatrienoic acid processing and degradation pathways in gestational diabetes mellitus (GDM) and metabolic traits in Chinese pregnant women. Methods A 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. Results The 12 SNPs in CYP2C8, CYP2C9, CYP2J2, and EPHX2 were significantly associated with GDM after adjusting for covariates (all P < 0.05). The GRS generated from these SNPs significantly correlated with GDM. Furthermore, a significant interaction between CYP2J2 and CYP2C8 in GDM (PInteraction = 0.014, ORInteraction= 0.61, 95%CI 0.41–0.90) was observed. Conclusion We 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.

Molecular Effect of Variants in Toll-like Receptor 4 Gene in Saudi Patients with Type 2 Diabetes Mellitus

“…Previously, multiple genome-wide association studies (GWAS), candidate genes, and linkage analysis studies investigated the relationship between genetic SNPs and the risk of T2DM, which were then utilized to identify high-risk individuals. GWAS began being used for screening patients with T2DM in 2000, and by 2016, over 60 SNPs of Asian and European ancestry had been identified [25,26]. TLR started being used in 1998 under the Sapporo criteria, with which antiphospholipid syndrome (APS) was proposed.…”

Multigenerational diabetes mellitus

“…Concurrently, metabolites of arachidonic acid produced by CYP450 enzymes, known as epoxyeicosatrienoic acids (EETs), are proposed to enhance insulin sensitivity and glucose metabolism. EETs are hydrolysed to less active forms by soluble epoxide hydrolase (sEH) encoded by EPHX2 ( 100 ). The predominant epoxygenases are CYP2J2, CYP2C8 and CYP2C9.…”

“…The predominant epoxygenases are CYP2J2, CYP2C8 and CYP2C9. The SNPs CYP2J2-rs76271683 and CYP2C8-rs11572177 have been associated with an increased risk of GDM, while the missense variant rs57699806 in EPHX2 has been associated with an increased risk of GDM and higher 1hPG and G AUC at OGTT ( 100 ). If multiple risk alleles are present, the risk of GDM may increase up to 1.8-fold ( 100 ).…”