基于MTHFR和MTRR基因多态性指导孕妇个体化补充叶酸

doi:10.5246/jcps.2025.11.078

摘要/Abstract

摘要：

孕期叶酸缺乏可能导致婴儿神经管畸形, 孕妇合理地补充叶酸可有效降低出生缺陷的风险。叶酸代谢相关基因的多态性影响着孕妇对叶酸的利用, 孕妇补充叶酸需要因人而异。本研究基于我院妇产科孕妇的叶酸代谢相关基因(MTHFR和MTRR)的多态性, 旨在阐明本地区人群的叶酸代谢能力相关基因遗传特征, 并探讨其与高危妊娠的关系和对指导孕妇个体化补充叶酸的作用。首先, 应用荧光杂交测序法对符合纳入和排除标准的患者进行MTHFR (rs1801133, rs1801131)和MTRR (rs1801394)的基因检测; 其次, 按照叶酸代谢相关基因检测结果将中度风险和高度风险的孕妇分为个体化组(按基因检测结果推荐的剂量补充叶酸)和对照组(按固定剂量400 μg/d补充叶酸); 最后, 通过来院复诊或电话随访, 记录两组孕妇的妊娠结局, 进一步探讨叶酸代谢相关基因指导孕妇个体化补充叶酸的作用。共有694名孕妇纳入研究, 其中377名中、高度风险者分别纳入个体化组172名、对照组205名, 两组比较无差异(P > 0.05)。叶酸代谢有风险组和无风险组孕妇的MTHFR (rs1801133)、MTHFR (rs1801131)、MTRR (rs1801394)基因型频率间的比较有显著性差异(P < 0.05), MTHFR (rs1801133)、MTRR (rs1801394)等位基因频率间比较也有显著性差异(P < 0.05), 而MTHFR (rs1801131)等位基因频率间的比较差异无统计学意义(P > 0.05)。个体化组与对照组孕妇的MTHFR (rs1801133)、MTHFR (rs1801131)、MTRR (rs1801394)基因型频率及等位基因频率比较均无统计学差异(P > 0.05)。个体化组出生缺陷、早产、自然流产、胎膜早破、羊水异常的发生率以及高血压发生比例均低于对照组(P < 0.05), 而两组的妊娠期糖尿病、妊娠期贫血、前置胎盘、胎盘早剥、脐带异常发生率比较则无统计学差异(P > 0.05)。因此, MTHFR和MTRR基因位点可能是本地区叶酸代谢障碍致高危妊娠风险人群疾病发生的潜在因素。此外, 检测叶酸代谢相关基因指导孕妇个体化补充叶酸能有效降低妊娠期合并症和并发症的发生, 有助于改善不良妊娠结局。

关键词: 叶酸, 基因多态性, 亚甲基四氢叶酸还原酶, 甲硫氨酸合酶还原酶, 妊娠结局

Abstract:

Folic acid (FA) deficiency during pregnancy is a significant risk factor for neural tube defects in infants. Appropriate supplementation with FA has been shown to effectively mitigate the risk of such congenital anomalies. However, genetic polymorphisms related to FA metabolism influence individual variations in FA utilization among pregnant women, highlighting the need for personalized supplementation strategies. This study aimed to explore the impact of genetic variations in FA metabolism-related genes, specifically methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), on tailoring FA supplementation during pregnancy. Using fluorescence hybridization sequencing, we analyzed polymorphisms in the MTHFR and MTRR genes among 694 pregnant women, who were divided into an individualized supplementation group and a control group. Pregnancy outcomes were monitored through outpatient visits and telephone follow-ups to evaluate the effect of personalized FA supplementation guided by genetic profiling. Notable differences in genotype frequencies of MTHFR (rs1801133, rs1801131) and MTRR (rs1801394) were observed between pregnant women with and without a heightened risk of FA metabolism disorders (P < 0.05). Similarly, allele frequencies of MTHFR (rs1801133) and MTRR (rs1801394) varied significantly among women with different risk profiles (P < 0.05). The results demonstrated that the individualized group exhibited significantly lower incidences of birth defects, preterm delivery, spontaneous abortion, premature rupture of membranes, abnormal amniotic fluid, and gestational hypertension compared to the control group (P < 0.05). These findings suggested that polymorphisms in MTHFR and MTRR genes were key determinants of FA metabolism and might contribute to adverse pregnancy outcomes in populations with a high prevalence of FA metabolism disorders. Furthermore, integrating genetic screening into FA supplementation protocols enabled more effective prevention of pregnancy complications and improved overall maternal and fetal health outcomes.

Key words: Folic acid, Gene polymorphism, Methylenetetrahydrofolate reductase, Methionine synthase reductase, Pregnancy outcome

Supporting:

庞晓军, 李倩倩, 黎东旺, 张莹珺. 基于MTHFR和MTRR基因多态性指导孕妇个体化补充叶酸[J]. 中国药学(英文版), 2025, 34(11): 1041-1050.

Xiaojun Pang, Qianqian Li, Dongwang Li, Yingjun Zhang. Personalized folic acid supplementation in pregnant women based on MTHFR and MTRR gene polymorphisms[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(11): 1041-1050.

图/表 8

Table 1. Risk rank of impaired FA metabolism.

Table 2. Comparison of genotype frequencies of pregnant women with different risks (n, %).

Table 3. Comparison of allele frequencies in pregnant women at different risks (n, %).

Table 4. Comparison of genotype frequency in different groups of pregnant women (n, %).

Table 5. Comparison of allele frequency in different groups of pregnant women (n, %).

Table 6. Comparison of pregnancy between the two groups (n, %).

Table 7. Comparison of comorbidity occurrence during pregnancy in both groups (n, %).

Table 8. Comparison of pregnancy complications occurrence in both groups (n, %).

参考文献 23

[1]	Gao, L.Y.; Ma, X.; Liu X. Research progress on the functions of vitamins in body. J. Chin. Pharm. Scis. 2016, 25, 329–341.
[2]	Tamura, T.; Picciano, M.F. Folate and human reproduction 2. Am. J. Clin. Nutr. 2006, 83, 993–1016.
[3]	Xue, J.; Li, L.; Zhang, M.L.; Yang, L.J.; Chen, W.J.; Song, L.; Chen, M. Study on the relationship between individualized supplementation of folic acid and health of assisted reproductive couples and fetal development. Mod. Diagn. Treat. 2022, 33, 3161–3164.
[4]	Antony, A.C. In utero physiology: role of folic acid in nutrient delivery and fetal development. Am. J. Clin. Nutr. 2007, 85, 598S–603S.
[5]	Zhang, T.R.; Yu, H.J.; Chen, Q.T.; Liu, M.W.; He, Q.Q. Effects of individualized folic acid supplementation on serum folic acid, homocysteine levels and neonatal outcome in pre-pregnancy women. Guangxi Med. J. 2020, 42, 1512–1516.
[6]	De-Regil, L.M.; Peña-Rosas, J.P.; Fernández-Gaxiola, A.C.; Rayco-Solon, P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst. Rev. 2015, 12, CD007950.
[7]	Zheng, J.S.; Guan, Y.H.; Zhao, Y.M.; Zhao, W.; Tang, X.J.; Chen, H.; Xu, M.L.; Wu, L.P.; Zhu, S.L.; Liu, H.J.; Huang, T.; Li, D. Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: a prospective cohort study. Br. J. Nutr. 2016, 115, 509–516.
[8]	Gaskins, A.J.; Rich-Edwards, J.W.; Hauser, R.; Williams, P.L.; Gillman, M.W.; Ginsburg, E.S.; Missmer, S.A.; Chavarro, J.E. Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Obstet. Gynecol. 2014, 124, 23–31.
[9]	Wu, H.C. Exploration on the significance of supplementing low-dose folic acid before and during pregnancy on pregnant women and fetuses. China Health Standard Manage. 2021, 12, 21–23.
[10]	Li, W.X.; Dai, S.X.; Zheng, J.J.; Liu, J.Q.; Huang, J.F. Homocysteine metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) jointly elevate the risk of folate deficiency. Nutrients. 2015, 7, 6670–6687.
[11]	Raigani, M.; Lakpour, N.; Soleimani, M.; Johari, B.; Sadeghi, M.R. A association of MTHFR C677T and MTRR A66G gene polymorphisms with Iranian male infertility and its effect on seminal folate and vitamin B12. Int. J. Fertil. Steril. 2021, 15, 20–25.
[12]	Chen, W.J.; Cu, D.D.; Chen Y.; Gu, J.H. Research progress on the effect of folic acid overdose during pregnancy on progeny. J. Med. Res. Combat Trauma Care. 2021, 34, 663–667.
[13]	Peng, R.; Zhang, H.; Zhang, Y. Recent advance in SNP identifying methods and individualized medication. J. Chin. Pharm. Sci. 2014, 23, 731–738.
[14]	Li, X.J.; Jiang, J.; Xu, M.; Xu, M.; Yang, Y.; Lu, W.; Yu, X.M.; Ma, J.L.; Pan, J.K. Individualized supplementation of folic acid according to polymorphisms of methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR) reduced pregnant complications. Gynecol. Obstet. Invest. 2015, 79, 107–112.
[15]	Yu, X.Y.; Diao, L.; Du, B.Y.; Wang, Y.; Xu, X.Q.; Yu, A.Q.; Zhao, J.M. Individualized folic acid supplementation based on MTHFR and MTRR gene polymorphisms reduces the risk of gestational diabetes mellitus in a Chinese population. Int. J. Clin. Exp. Pathol. 2023, 16, 150–157.
[16]	McNulty, H.; Rollins, M.; Cassidy, T.; Caffrey, A.; Marshall, B.; Dornan, J.; McLaughlin, M.; McNulty, B.A.; Ward, M.; Strain, J.J.; Molloy, A.M.; Lees-Murdock, D.J.; Walsh, C.P.; Pentieva, K. Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial). BMC Med. 2019, 17, 196.
[17]	Menezo, Y.; Elder, K.; Clement, A.; Clement, P. Folic acid, folinic acid, 5 methyl TetraHydroFolate supplementation for mutations that affect epigenesis through the folate and one-carbon cycles. Biomolecules. 2022, 12, 197.
[18]	Caffrey, A.; Irwin, R.E.; McNulty, H.; Strain, J.J.; Lees-Murdock, D.J.; McNulty, B.A.; Ward, M.; Walsh, C.P.; Pentieva, K. Gene-specific DNA methylation in newborns in response to folic acid supplementation during the second and third trimesters of pregnancy: epigenetic analysis from a randomized controlled trial. Am. J. Clin. Nutr. 2018, 107, 566–575.
[19]	Caffrey, A.; McNulty, H.; Rollins, M.; Prasad, G.; Gaur, P.; Talcott, J.B.; Witton, C.; Cassidy, T.; Marshall, B.; Dornan, J.; Moore, A.J.; Ward, M.; Strain, J.J.; Molloy, A.M.; McLaughlin, M.; Lees-Murdock, D.J.; Walsh, C.P.; Pentieva, K. Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial. BMC Med. 2021, 19, 73.
[20]	Ondičová, M.; Irwin, R.E.; Thursby, S.J.; Hilman, L.; Caffrey, A.; Cassidy, T.; McLaughlin, M.; Lees-Murdock, D.J.; Ward, M.; Murphy, M.; Lamers, Y.; Pentieva, K.; McNulty, H.; Walsh, C.P. Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms. Clin. Epigenetics. 2022, 14, 63.
[21]	Murray, L.K.; Smith, M.J.; Jadavji, N.M. Maternal oversupplementation with folic acid and its impact on neurodevelopment of offspring. Nutr. Rev. 2018, 76, 708–721.
[22]	Patti, M.A.; Braun, J.M.; Arbuckle, T.E.; MacFarlane, A.J. Associations between folic acid supplement use and folate status biomarkers in the first and third trimesters of pregnancy in the Maternal–Infant Research on Environmental Chemicals (MIREC) Pregnancy Cohort Study. Am. J. Clin. Nutr. 2022, 116, 1852–1863.
[23]	Zhang, X.J.; Liu, J.F.; Jin, Y.S.; Yang, S.; Song, Z.J.; Jin, L.; Wang, L.L.; Ren, A.G. Folate of pregnant women after a nationwide folic acid supplementation in China. Matern. Child Nutr. 2019, 15, e12828.