Association analysis of MTHFR (C677T, A1298C) and MTRR (A66G) gene polymorphisms on susceptibility to gestational diabetes mellitus in Chinese pregnant women.

Abstract

Gestational diabetes mellitus (GDM) is a common pregnancy complication with rising incidence and adverse maternal-fetal outcomes. Genetic polymorphisms in folate metabolism genes may influence GDM susceptibility through homocysteine pathway alterations. To investigate the associations between MTHFR (C677T, A1298C) and MTRR (A66G) polymorphisms and GDM risk, including gene‒gene interactions, in Chinese Han pregnant women, this retrospective cohort study analyzed 1312 Chinese Han pregnant women. The MTHFR C677T, A1298C, and MTRR A66G polymorphisms were genotyped using allele-specific PCR. Polymorphism-GDM associations were assessed using logistic regression, adjusting for maternal age, prepregnancy BMI, and folate intake. Gene‒gene interactions were evaluated using multiplicative interaction models. After confounder adjustment, the MTHFR 677TT genotype was associated with GDM (OR 1.89, 95% CI 1.24-2.93) compared to wild-type. The MTRR 66AG and 66GG genotypes were associated with GDM, with ORs of 2.73 (95% CI: 1.93-3.89) and 3.10 (95% CI: 1.72-5.41), respectively. Significant gene‒gene interactions were observed between MTHFR C677T & A1298C (OR 2.22, 95% CI 1.25-4.23 for TT/AA combination) and MTHFR C677T & MTRR A66G (OR 6.06, 95% CI 3.48-14.10 for TT/AG combination), indicating synergistic effects that surpass the expected multiplicative combination of individual polymorphism effects. MTHFR C677T and MTRR A66G polymorphisms independently and interactively increase GDM odds in Chinese Han women, enabling personalized risk prediction and targeted prevention.