母亲MTHFD1及MTHFD2基因多态性与子代先天性心脏病的关联

Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring

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。

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.