MTHFR variants modify the association between pre-pregnancy BMI and postpartum abnormal glucose tolerance among women with gestational diabetes mellitus

Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and obesity are associated with glucose metabolism dysregulation. This study aimed to investigate the individual and joint effects of MTHFR gene polymorphisms and pre-pregnancy body mass index (pre-BMI) status on postpartum abnormal glucose tolerance (PAGT) risk among women with gestational diabetes mellitus (GDM). This retrospective study enrolled 1181 women with GDM who underwent a postpartum oral glucose tolerance testing for 6–12 weeks in Guangzhou, China. The association between MTHFR gene polymorphism and pre-BMI status with PAGT risk was assessed using logistic regression models, followed by stratified analyses. Among the included women with GDM, the overall prevalence of PAGT was 28.96%, and the prevalence of pre-pregnancy obesity was 4.23%. Pre-pregnancy obesity and carriage of the MTHFR A1298C AC + CC genotype were independently associated with a significantly elevated risk of PAGT. Stratified analyses by MTHFR variants dominant models revealed that women with obesity carrying the MTHFR C677T CT + TT genotype had an elevated risk of PAGT (odds ratio OR = 3.99, 95% confidence interval CI: 1.21–13.18). Among A1298C AA genotype carriers, pre-pregnancy obesity was associated with a 4.85-fold higher risk of PAGT (95% CI 1.35–17.41), whereas pre-pregnancy underweight correlated with a significantly reduced PAGT risk (OR = 0.37, 95% CI 0.14–0.99). Furthermore, in the normal weight subgroup, women harboring the MTHFR A1298C AA genotype combined with the C677T CT + TT genotype had a significantly decreased risk of PAGT (OR = 0.59, 95% CI 0.35–0.98), compared with those carrying the MTHFR A1298C AC + CC genotype combined with the C677T CT genotype. Pre-pregnancy obesity is an independent risk factor for PAGT in women with GDM, and this association could be modified by MTHFR gene polymorphisms. Further large-scale prospective studies are warranted to evaluate whether genotype-guided folic acid supplementation can reduce PAGT risk in high-risk women with GDM, particularly those with pre-pregnancy obesity. Not applicable.