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

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.

妊娠糖尿病（Gestational diabetes mellitus, GDM）是一种常见的妊娠并发症，发病率呈逐年上升态势，可对母婴结局产生不良影响。叶酸代谢相关基因的遗传多态性可能通过改变同型半胱氨酸通路，进而影响妊娠糖尿病的发病易感性。为探讨中国汉族孕妇群体中，亚甲基四氢叶酸还原酶（MTHFR）C677T、A1298C位点以及甲硫氨酸合酶还原酶（MTRR）A66G位点的遗传多态性与妊娠糖尿病发病风险的关联（包括基因-基因交互作用），本回顾性队列研究共纳入1312名中国汉族孕妇进行分析。研究采用等位基因特异性PCR（allele-specific PCR）对MTHFR C677T、A1298C及MTRR A66G位点进行基因分型。通过logistic回归模型分析多态性与妊娠糖尿病的关联，并校正孕妇年龄、孕前体重指数（BMI）及叶酸摄入等混杂因素；同时采用相乘交互作用模型评估基因-基因交互效应。校正混杂因素后，与野生型相比，MTHFR 677TT基因型与妊娠糖尿病发病风险显著相关（优势比OR=1.89，95%置信区间CI：1.24~2.93）。MTRR 66AG与66GG基因型同样与妊娠糖尿病发病风险相关，对应的优势比分别为2.73（95%CI：1.93~3.89）与3.10（95%CI：1.72~5.41）。研究观察到MTHFR C677T与A1298C位点间（TT/AA联合基因型的OR值为2.22，95%CI：1.25~4.23）、MTHFR C677T与MTRR A66G位点间（TT/AG联合基因型的OR值为6.06，95%CI：3.48~14.10）存在显著的基因-基因交互作用，提示二者存在协同效应，其交互作用强度超过单个多态位点效应的相乘组合预期值。综上，在中国汉族孕妇群体中，MTHFR C677T与MTRR A66G位点的遗传多态性可通过独立效应与交互效应共同升高妊娠糖尿病的发病风险，该发现可为妊娠糖尿病的个性化风险预测与精准预防提供理论支撑。