国际妇产科学杂志 ›› 2021, Vol. 48 ›› Issue (2): 191-195.doi: 10.12280/gjfckx.20200659
收稿日期:
2020-07-20
出版日期:
2021-04-15
发布日期:
2021-04-16
通讯作者:
李增彦
E-mail:li_zengyan@sina.com
基金资助:
YUAN Bi-bo, WANG Qiu-xia, LI Zeng-yan△(), MA Yan-hong
Received:
2020-07-20
Published:
2021-04-15
Online:
2021-04-16
Contact:
LI Zeng-yan
E-mail:li_zengyan@sina.com
摘要:
复发性流产的定义不同国家和地区在流产次数及流产孕周等内容上仍未达成统一的标准,其病因错综复杂,是近几年的研究热点,随着研究不断深入,目前已明确多方面致病因素,但仍有多数患者的病因尚未明确,给临床诊疗带来极大的困难。叶酸作为一碳单位的载体,是核酸合成和DNA修复的重要物质,其代谢异常可通过干扰DNA的甲基化和合成、影响同型半胱氨酸水平导致相关疾病的发生,而叶酸代谢通路受相关酶活性的调节,关键酶基因存在遗传多态性,其通过改变酶活性影响叶酸代谢过程;近期越来越多研究证实叶酸代谢异常可引起复发性流产发生风险增加,而通过叶酸干预可改善妊娠结局,降低复发性流产的发生率,但其作用机制尚存争议。综述叶酸代谢障碍与复发性流产的相关性研究进展,为复发性流产的诊疗提供帮助。
袁碧波, 王秋霞, 李增彦, 马艳红. 叶酸代谢障碍与复发性流产相关性研究进展[J]. 国际妇产科学杂志, 2021, 48(2): 191-195.
YUAN Bi-bo, WANG Qiu-xia, LI Zeng-yan, MA Yan-hong. Research Progress on the Relationship between Folate Metabolism Disorder and Recurrent Spontaneous Abortion[J]. Journal of International Obstetrics and Gynecology, 2021, 48(2): 191-195.
图1 叶酸代谢途径[5] 注:Cys 半胱氨酸,CBS 胱硫醚β合成酶,DHF 二氢叶酸,DNMTs DNA甲基转移酶,dTMP 胸腺嘧啶脱氧核苷酸,dUMP 尿嘧啶脱氧核苷酸,GSH:谷胱甘肽,HCY 同型半胱氨酸,Met 蛋氨酸,MAT 蛋氨酸腺苷转移,5-MTHF 5-亚甲基四氢叶酸,5,10-MTHF 5,10-亚甲基四氢叶酸,MTHFR 亚甲基四氢叶酸还原酶,MTR 蛋氨酸合成酶,MTRR 蛋氨酸合成酶还原酶,RFC1 还原叶酸载体,SAH S-腺苷同型半胱氨酸,SAM S-腺苷蛋氨酸,THF 四氢叶酸,TS 胸苷酸合成酶。
[1] |
Definitions of infertility and recurrent pregnancy loss: a committee opinion[J]. Fertil Steril, 2020,113(3):533-535. doi: 10.1016/j.fertnstert.2019.11.025.
doi: 10.1016/j.fertnstert.2019.11.025 pmid: 32115183 |
[2] | Royal College of Obstetricians and Gynaecologists. The Investigation and Treatment of Couples with Recurrent First-trimester and Second-trimester Miscarriage. RCOG green-top guideline No.17[EB/OL].[2011]. http://rayal-gynecologist.com/gynecology%20guildlines/GTG17recurrentmiscarriage.pdf. |
[3] | 中华医学会妇产科学分会产科学组. 复发性流产诊治的专家共识[J]. 中华妇产科杂志, 2016,51(1):3-9. doi: 10.3760/cma.j.issn.0529-567x.2016.01.002. |
[4] |
Hong Li Y, Marren A. Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice[J]. Aust J Gen Pract, 2018,47(7):432-436. doi: 10.31128/AJGP-01-18-4459.
pmid: 30114870 |
[5] |
Coppedè F. One-carbon metabolism and Alzheimer′s disease: focus on epigenetics[J]. Curr Genomics, 2010,11(4):246-260. doi: 10.2174/138920210791233090.
pmid: 21119889 |
[6] | Finkelstein JD. The metabolism of homocysteine: pathways and regulation[J]. Eur J Pediatr, 1998,157 Suppl 2: S40-44. doi: 10.1007/pl00014300. |
[7] |
Moll S, Varga EA. Homocysteine and MTHFR Mutations[J]. Circulation, 2015,132(1):e6-9. doi: 10.1161/CIRCULATIONAHA.114.013311.
doi: 10.1161/CIRCULATIONAHA.114.013311 pmid: 26149435 |
[8] | Dean L. Methylenetetrahydrofolate Reductase Deficiency[M/OL]// Pratt VM, McLeod HL, Rubinstein WS, et al. Medical Genetics Summaries. Bethesda (MD):National Center for Biotechnology Information (US),2012. [2012-3-8] (2016-10-27). http://europepmc.org/article/MED/28520345. |
[9] |
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase[J]. Nat Genet, 1995,10(1):111-113. doi: 10.1038/ng0595-111.
doi: 10.1038/ng0595-111 pmid: 7647779 |
[10] |
van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?[J]. Am J Hum Genet, 1998,62(5):1044-1051. doi: 10.1086/301825.
pmid: 9545395 |
[11] |
Crider KS, Zhu JH, Hao L, et al. MTHFR 677C->T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation[J]. Am J Clin Nutr, 2011,93(6):1365-1372. doi: 10.3945/ajcn.110.004671.
doi: 10.3945/ajcn.110.004671 pmid: 21508090 |
[12] |
Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review[J]. Am J Epidemiol, 2000,151(9):862-877. doi: 10.1093/oxfordjournals.aje.a010290.
doi: 10.1093/oxfordjournals.aje.a010290 pmid: 10791559 |
[13] |
Cao Y, Xu J, Zhang Z, et al. Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: a meta-analysis[J]. Gene, 2013,514(2):105-111. doi: 10.1016/j.gene.2012.10.091.
pmid: 23201418 |
[14] | 刘宇岩, 杨博逸, 李永芳, 等. 5,10-亚甲基四氢叶酸还原酶C677T基因多态性与原因不明复发性流产关联的Meta分析[J]. 中国全科医学, 2013,16(25):2992-2997. doi: 10.3969/j.issn.1007-9572.2013.25.024. |
[15] |
Olteanu H, Munson T, Banerjee R. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase[J]. Biochemistry, 2002,41(45):13378-13385. doi: 10.1021/bi020536s.
pmid: 12416982 |
[16] | 王伟华, 王凤菊, 刘伟. MTRR基因A66G多态性与高同型半胱氨酸血症的相关性研究[J]. 山东医药, 2007,47(25):54-55. doi: 10.3969/j.issn.1002-266X.2007.25.024. |
[17] | 安妮, 张阳, 宋沧桑. 叶酸代谢相关基因多态性与其个体化补充的研究进展[J]. 中国药房, 2017,28(17):2444-2448. doi: 10.6039/j.issn.1001-0408.2017.17.39. |
[18] |
Li D, Zhao Q, Zhang C, et al. Associations of MTRR A66G polymorphism and promoter methylation with ischemic stroke in patients with hyperhomocysteinemia[J]. J Gene Med, 2020,22(5):e3170. doi: 10.1002/jgm.3170.
doi: 10.1002/jgm.3170 pmid: 32034842 |
[19] | 汪希鹏, 林其德, 马政文, 等. 原因不明复发性流产患者血中亚甲基四氢叶酸还原酶基因C677T和A1298C位点突变的研究[J]. 中华妇产科杂志, 2004,39(4):238-241. doi: 10.3760/j.issn:0529-567X.2004.04.007. |
[20] | 秦奇, 有风芝, 张仪. 亚甲基四氢叶酸还原酶和甲硫氨酸合成酶还原酶基因多态性与胚胎停止发育的相关性研究[J]. 重庆医科大学学报, 2016,41(3):243-246. doi: 10.13406/j.cnki.cyxb.000745. |
[21] |
Chen H, Yang X, Lu M. Methylenetetrahydrofolate reductase gene polymorphisms and recurrent pregnancy loss in China: a systematic review and meta-analysis[J]. Arch Gynecol Obstet, 2016,293(2):283-290. doi: 10.1007/s00404-015-3894-8.
doi: 10.1007/s00404-015-3894-8 pmid: 26399758 |
[22] | 赵雪杰, 李晓娜, 孙茗, 等. 叶酸代谢相关酶MTHFR、MTRR基因多态性与不良孕产史的关系[J]. 检验医学与临床, 2019,16(19):2761-2763. doi: 10.3969/j.issn.1672-9455.2019.19.003. |
[23] | 谢晓媛, 张颖, 辛力, 等. 叶酸代谢酶MTHFR、MTRR基因多态性与原因不明复发性流产的关系[J]. 天津医药, 2016,44(10):1243-1246. doi: 10.11958/20160099. |
[24] | 王连, 郝胜菊, 闫有圣, 等. 血浆Hcy水平及MTHFR和MTRR基因多态性与复发性流产的相关性研究[J]. 中国优生与遗传杂志, 2017,25(7):18-19,17. |
[25] | 唐黛丽, 吴忠琴, 金亚清, 等. MTHFR C677T基因多态性及血浆HCY与复发性流产的关系[J]. 中国优生与遗传杂志, 2016,24(6):15-16,3. |
[26] |
Lin Z, Li Q, Sun Y, et al. Interactions between genetic variants involved in the folate metabolic pathway and serum lipid, homocysteine levels on the risk of recurrent spontaneous abortion[J]. Lipids Health Dis, 2019,18(1):143. doi: 10.1186/s12944-019-1083-7.
pmid: 31200713 |
[27] |
Mazokopakis EE, Papadomanolaki MG. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms among Greek women with medical history of recurrent pregnancy loss[J]. Arch Gynecol Obstet, 2020,302(6):1555-1556. doi: 10.1007/s00404-020-05485-7.
doi: 10.1007/s00404-020-05485-7 pmid: 32146534 |
[28] | 熊雯, 谢聪, 黄娟, 等. 复发性流产患者叶酸代谢水平及叶酸干预对妊娠的影响研究[J]. 中国优生与遗传杂志, 2016,24(1):77-80. |
[29] | 马庆荣. 复发性流产患者叶酸代谢水平及叶酸干预对妊娠的影响观[J]. 饮食保健, 2019,6(2):59-60. doi: 10.3969/j.issn.2095-8439.2019.02.073. |
[30] |
Puri M, Kaur L, Walia GK, et al. MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among North Indian women[J]. J Perinat Med, 2013,41(5):549-554. doi: 10.1515/jpm-2012-0252.
doi: 10.1515/jpm-2012-0252 pmid: 23612630 |
[31] | 杨修远, 潘月龙. 叶酸与肿瘤的研究进展[J]. 实用肿瘤杂志, 2017,32(2):187-191. |
[32] | 倪娟. 叶酸、核黄素及MTHFR多态性对人类淋巴细胞8和17号染色体非整倍体的影响[D]. 昆明 :云南师范大学, 2008. |
[33] |
James SJ, Pogribna M, Pogribny IP, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome[J]. Am J Clin Nutr, 1999,70(4):495-501. doi: 10.1093/ajcn/70.4.495.
doi: 10.1093/ajcn/70.4.495 pmid: 10500018 |
[34] | Wang X, Thomas P, Xue J, et al. Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21[J]. Mutat Res, 2004,551(1/2):167-180. doi: 10.1016/j.mrfmmm.2004.03.008. |
[35] | Sadiq MF, Al-Refai EA, Al-Nasser A, et al. Methylenetetrahydrofolate reductase polymorphisms C677T and A1298C as maternal risk factors for Down syndrome in Jordan[J]. Genet Test Mol Biomarkers, 2011,15(1/2):51-57. doi: 10.1089/gtmb.2010.0057. |
[36] |
Kaur A, Kaur A. Maternal MTHFR polymorphism (677 C-T) and risk of Down's syndrome child: meta-analysis[J]. J Genet, 2016,95(3):505-513. doi: 10.1007/s12041-016-0657-7.
doi: 10.1007/s12041-016-0657-7 pmid: 27659321 |
[37] | 姜育燊, 孟帅, 姜傥, 等. 中国汉族人群MTHFR多态性与唐氏综合征风险Meta分析[J]. 中国妇幼健康研究, 2019,30(12):1561-1566. doi: 10.3969/j.issn.1673-5293.2019.12.016. |
[38] |
Izci Ay O, Ay ME, Erdal ME, et al. Folate metabolism gene polymorphisms and risk for down syndrome offspring in Turkish women[J]. Genet Test Mol Biomarkers, 2015,19(4):191-197. doi: 10.1089/gtmb.2014.0262.
pmid: 25671679 |
[39] |
Wu X, Wang X, Chan Y, et al. Folate metabolism gene polymorphisms MTHFR C677T and A1298C and risk for Down syndrome offspring: a meta-analysis[J]. Eur J Obstet Gynecol Reprod Biol, 2013,167(2):154-159. doi: 10.1016/j.ejogrb.2012.11.022.
doi: 10.1016/j.ejogrb.2012.11.022 pmid: 23295071 |
[40] |
Blanco-Muñoz J, Lacasaña M, Gamboa R, et al. Interaction between MTHFR 677C>T, PON1 192Q>R and PON1 55L>M polymorphisms and its effect on non-recurrent spontaneous abortion in Mexican women[J]. Gene, 2019,689:69-75. doi: 10.1016/j.gene.2018.11.093.
doi: 10.1016/j.gene.2018.11.093 pmid: 30529100 |
[41] |
Yang M, Gong T, Lin X, et al. Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis[J]. Mutagenesis, 2013,28(6):661-671. doi: 10.1093/mutage/get045.
pmid: 24068460 |
[42] |
da Silva LR, Vergani N, Galdieri Lde C, et al. Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil[J]. Am J Med Genet A, 2005,135(3):263-267. doi: 10.1002/ajmg.a.30591.
pmid: 15889417 |
[43] | 董燕燕, 陈光亮. 高同型半胱氨酸血症危害及致病机制研究进展[J]. 中国药理学通报, 2014,30(9):1205-1208. |
[44] | 郭志霞, 赵兴胜. 同型半胱氨酸与冠心病发病机制及相关性研究进展[J]. 医学综述, 2019,25(22):4477-4482. doi: 10.3969/j.issn.1006-2084.2019.22.022. |
[45] |
Eskes TK. Clotting disorders and placental abruption: homocysteine--a new risk factor[J]. Eur J Obstet Gynecol Reprod Biol, 2001,95(2):206-212. doi: 10.1016/s0301-2115(00)00492-9.
doi: 10.1016/s0301-2115(00)00492-9 pmid: 11301173 |
[46] | 李孟兰, 林宁, 石慧, 等. 血浆同型半胱氨酸与先兆流产、复发性流产及继发性不孕的关系[J]. 中国医药导报, 2018,15(33):64-67. |
[47] | 赵宗霞, 高燕, 张建华, 等. 同型半胱氨酸及抗凝血酶Ⅲ与复发性流产的相关性[J]. 中国优生与遗传杂志, 2017,25(10):60-61. |
[48] | 周艳荷, 刘志辉, 冯书梅, 等. 血清同型半胱氨酸水平与复发性流产发生的相关性研究[J]. 中国医药科学, 2018,8(22):75-77. doi: 10.3969/j.issn.2095-0616.2018.22.023. |
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