母亲<italic>MTHFD1</italic>及<italic>MTHFD2</italic>基因多态性与子代先天性心脏病的关联

doi:10.7499/j.issn.1008-8830.2203002

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摘要目的探讨母亲亚甲基四氢叶酸脱氢酶（methylenetetrahydrofolate dehydrogenase，MTHFD）1、2（MTHFD1、MTHFD2）基因多态性与子代先天性心脏病（congenital heart disease，CHD）的关联。方法采用以医院为基础的病例对照研究，选取2017年11月至2020年3月在湖南省儿童医院就诊的683例单纯CHD患儿的母亲作为病例组，选取同时间段内就诊于同一家医院并排除任何先天畸形的740例儿童的母亲作为对照组。通过问卷调查，收集研究对象的相关暴露信息。完成调查问卷后，采集母亲5 mL静脉血，用于MTHFD1、MTHFD2基因多态性的检测。采用多因素logistic回归模型分析MTHFD1、MTHFD2基因多态性与CHD的关联；采用Haploview 4.2软件的四配子检验法构建单倍型，评估单倍型与CHD的关联；并采用广义多因子降维法和logistic回归法分析基因-基因交互作用与CHD的关联。结果多因素logistic回归分析显示，母亲MTHFD1基因rs11849530位点（GA vs AA：OR=1.49；GG vs AA：OR=2.04）和rs1256142位点（GA vs GG：OR=2.34；AA vs GG：OR=3.25）显著增加子代CHD的发生风险（P<0.05），而母亲MTHFD1基因rs1950902位点（AA vs GG：OR=0.57）和MTHFD2基因rs1095966位点（CA vs CC：OR=0.68）显著降低子代CHD的发生风险（P<0.05）。母亲携带单倍型G-G-G（OR=1.86）、G-A-G（OR=1.35）显著增加子代CHD的发生风险（P<0.05）。交互作用分析显示，母亲MTHFD基因2个位点（MTHFD1 rs1950902、MTHFD1 rs2236222）的一阶交互作用及3个位点（MTHFD1 rs1950902、MTHFD1 rs1256142、MTHFD2 rs1095966）的二阶交互作用可能与CHD的发生风险存在关联（P<0.05）。结论母亲MTHFD1、MTHFD2基因多态性及其单倍型，以及2个位点（MTHFD1 rs1950902、MTHFD1 rs2236222）和3个位点（MTHFD1 rs1950902、MTHFD1 rs1256142、MTHFD2 rs1095966）的交互作用与子代CHD的发生相关。

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	陈倩
	黄鹏
	宋欣俐
	刘亦萍
	孙梦婷
	王婷婷
	张森茂
	秦家碧

关键词 ：先天性心脏病, 亚甲基四氢叶酸脱氢酶, 病例对照研究, 单倍型, 基因-基因交互作用, 子代

Abstract：Objective To study the association of maternal methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) gene polymorphisms with congenital heart disease (CHD) in offspring. Methods A hospital-based case-control study was conducted. The mothers of 683 children with CHD alone who attended Hunan Children's Hospital, from November 2017 to March 2020 were enrolled as the case group, and the mothers of 740 healthy children who attended the same hospital during the same period and did not have any deformity were enrolled as the control group. A questionnaire survey was performed to collect related exposure data, and then venous blood samples (5 mL) were collected from the mothers to detect MTHFD1 and MTHFD2 gene polymorphisms. A multivariate logistic regression analysis was used to evaluate the association of MTHFD1 and MTHFD2 gene polymorphisms with CHD. The four-gamete test in Haploview 4.2 software was used to construct haplotypes and evaluate the association between haplotypes and CHD. The generalized multifactor dimensionality reduction method and logistic regression analysis were used to examine gene-gene interaction and its association with CHD. Results The multivariate logistic regression analysis showed that maternal MTHFD1 gene polymorphisms at rs11849530 (GA vs AA: OR=1.49; GG vs AA: OR=2.04) and at rs1256142 (GA vs GG: OR=2.34; AA vs GG: OR=3.25) significantly increased the risk of CHD in offspring (P<0.05), while maternal MTHFD1 gene polymorphisms at rs1950902 (AA vs GG: OR=0.57) and MTHFD2 gene polymorphisms at rs1095966 (CA vs CC: OR=0.68) significantly reduced the risk of CHD in offspring (P<0.05). The haplotypes of G-G-G (OR=1.86) and G-A-G (OR=1.35) in mothers significantly increased the risk of CHD in offspring (P<0.05). The gene-gene interaction analyses showed that the first-order interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and the second-order interaction involving MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966 might be associated with risk of CHD (P<0.05). Conclusions Maternal MTHFD1 and MTHFD2 gene polymorphisms and their haplotypes, as well as the interaction between MTHFD1 rs1950902 and MTHFD1 rs2236222 and between MTHFD1 rs1950902, MTHFD1 rs1256142, and MTHFD2 rs1095966, are associated with the risk of CHD in offspring.

Key words： Congenital heart disease Methylenetetrahydrofolate dehydrogenase Case-control study Haplotype Gene-gene interaction Offspring

收稿日期: 2022-03-02

基金资助:国家自然科学基金项目（81803313、82073653）；湖南省重点研发计划项目（2018SK2063）；湖南省科技人才托举工程项目（2020TJ-N07）；国家卫生健康委员会出生缺陷研究与预防重点实验室（湖南省妇幼保健院）开放课题（KF2020006）；湖南省自然科学基金项目（2018JJ2551）。

通讯作者: 秦家碧，男，教授。Email：qinjiabi@csu.edu.cn。 E-mail: qinjiabi@csu.edu.cn

作者简介: 陈倩，女，硕士研究；

引用本文:

陈倩,黄鹏,宋欣俐等. 母亲MTHFD1及MTHFD2基因多态性与子代先天性心脏病的关联[J]. 中国当代儿科杂志, 2022, 24(7): 797-805.

CHEN Qian,HUANG Peng,SONG Xin-Li et al. Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring[J]. CJCP, 2022, 24(7): 797-805.

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	Rossano JW. Congenital heart disease: a global public health concern[J]. Lancet Child Adolesc Health, 2020, 4(3): 168-169. PMID: 31978370. DOI: 10.1016/S2352-4642(19)30429-8.
	Parnell AS, Correa A. Analyses of trends in prevalence of congenital heart defects and folic acid supplementation[J]. J Thorac Dis, 2017, 9(3): 495-500. PMID: 28449454. PMCID: PMC5393985. DOI: 10.21037/jtd.2017.03.16.
	Liu Y, Chen S, Zühlke L, et al. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies[J]. Int J Epidemiol, 2019, 48(2): 455-463. PMID: 30783674. PMCID: PMC6469300. DOI: 10.1093/ije/dyz009.
	4 王蕾, 王海丽, 常明秀, 等. 孕前及孕早期母体因素与子代复杂先天性心脏病的相关性研究[J]. 现代预防医学, 2020, 47(4): 739-742.
	Moreau JLM, Kesteven S, Martin EMMA, et al. Gene-environment interaction impacts on heart development and embryo survival[J]. Development, 2019, 146(4): dev172957. PMID: 30787001. DOI: 10.1242/dev.172957.
	Stanhewicz AE, Kenney WL. Role of folic acid in nitric oxide bioavailability and vascular endothelial function[J]. Nutr Rev, 2017, 75(1): 61-70. PMID: 27974600. PMCID: PMC5155615. DOI: 10.1093/nutrit/nuw053.
	7 赵刘碧琦, 徐子力, 刘宗谕, 等. 叶酸代谢通路相关酶基因多态性与先天性心脏病的关系研究[J]. 中国妇幼保健, 2019, 34(14): 3371-3374. DOI: 10.7620/zgfybj.j.issn.1001-4411.2019.14.70.
	Qu Y, Lin S, Zhuang J, et al. First-trimester maternal folic acid supplementation reduced risks of severe and most congenital heart diseases in offspring: a large case-control study[J]. J Am Heart Assoc, 2020, 9(13): e015652. PMID: 32613868. PMCID: PMC7670504. DOI: 10.1161/JAHA.119.015652.
	Song X, Li Q, Diao J, et al. Association of MTHFD1 gene polymorphisms and maternal smoking with risk of congenital heart disease: a hospital-based case-control study[J]. BMC Pregnancy Childbirth, 2022, 22(1): 88. PMID: 35100977. PMCID: PMC8805321. DOI: 10.1186/s12884-022-04419-2.
	10 何焕. MTHFD2在食管鳞癌中的表达及其临床预后意义[D]. 合肥: 安徽医科大学, 2020.
	Tedeschi PM, Scotto KW, Kerrigan J, et al. MTHFD2—a new twist?[J]. Oncotarget, 2016, 7(7): 7368-7369. PMID: 26848977. PMCID: PMC4884922. DOI: 10.18632/oncotarget.7147.
	Christensen KE, Mackenzie RE. Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases[J]. Vitam Horm, 2008, 79: 393-410. PMID: 18804703. DOI: 10.1016/S0083-6729(08)00414-7.
	Khatami M, Ratki FM, Tajfar S, et al. Relationship of the MTHFD1 (rs2236225), eNOS (rs1799983), CBS (rs2850144) and ACE (rs4343) gene polymorphisms in a population of Iranian pediatric patients with congenital heart defects[J]. Kaohsiung J Med Sci, 2017, 33(9): 442-448. PMID: 28865601. DOI: 10.1016/j.kjms.2017.05.016.
	Wang B, Liu M, Yan W, et al. Association of SNPs in genes involved in folate metabolism with the risk of congenital heart disease[J]. J Matern Fetal Neonatal Med, 2013, 26(18): 1768-1777. PMID: 23701284. DOI: 10.3109/14767058.2013.799648.
	Christensen KE, Rohlicek CV, Andelfinger GU, et al. The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects[J]. Hum Mutat, 2009, 30(2): 212-220. PMID: 18767138. DOI: 10.1002/humu.20830.
	Huang J, Mei J, Jiang L, et al. MTHFR rs1801133 C>T polymorphism is associated with an increased risk of tetralogy of Fallot[J]. Biomed Rep, 2014, 2(2): 172-176. PMID: 24649091. PMCID: PMC3917760. DOI: 10.3892/br.2014.222.
	Jiang YC, Kuang LL, Sun SN, et al. Association of genetic polymorphisms of de novo nucleotide biosynthesis with increased CHD susceptibility in the northern Chinese population[J]. Clin Genet, 2017, 91(5): 748-755. PMID: 27659940. DOI: 10.1111/cge.12874.
	18 许晶. 基因区域多态性与先天性心脏病发病关系研究[D]. 南京: 南京医科大学, 2010.
	Xu J, Xu X, Xue L, et al. MTHFR c.1793G>A polymorphism is associated with congenital cardiac disease in a Chinese population[J]. Cardiol Young, 2010, 20(3): 318-326. PMID: 20374669. DOI: 10.1017/S1047951110000247.
	Cheng J, Zhu WL, Dao JJ, et al. Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect[J]. Biomed Environ Sci, 2005, 18(1): 58-64. PMID: 15861780.
	Shaw GM, Lu W, Zhu H, et al. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects[J]. BMC Med Genet, 2009, 10: 49. PMID: 19493349. PMCID: PMC2700092. DOI: 10.1186/1471-2350-10-49.
	22 张若, 马慧, 闫慧, 等. 围孕期妇女4种生活因素与新生儿先天性心脏病关系的广义线性模型分析[J]. 西安交通大学学报(医学版), 2017, 38(3): 332-336. DOI: 10.7652/jdyxb201703003.
	Zhu Z, Leung GKK. More than a metabolic enzyme: MTHFD2 as a novel target for anticancer therapy?[J]. Front Oncol, 2020, 10: 658. PMID: 32411609. PMCID: PMC7199629. DOI: 10.3389/fonc.2020.00658.
	Rosenquist TH. Folate, homocysteine and the cardiac neural crest[J]. Dev Dyn, 2013, 242(3): 201-218. PMID: 23335187. DOI: 10.1002/dvdy.23922.
	25 王婷婷. 先天性心脏病的影响因素及预测模型研究[D]. 长沙: 中南大学, 2020.