Association of MTHFD1 gene polymorphisms and maternal smoking with risk of congenital heart disease: a hospital-based case-control study

Abstract

Background MTHFD1 gene may affect the embryonic development by elevated homocysteine levels, DNA synthesis and DNA methylation, but limited number of genetic variants of MTHFD1 gene was focused on the association with congenital heart disease (CHD). This study examined the role of MTHFD1 gene and maternal smoking on infant CHD risk, and investigated their interaction effects in Chinese populations. Methods A case-control study of 464 mothers of CHD infants and 504 mothers of health controls was performed. The exposures of interest were maternal tobacco exposure, single nucleotide polymorphisms (SNPs) of maternal MTHFD1 gene. The logistic regression model was used for accessing the strength of association. Results Mothers exposed to secondhand smoke during 3 months before pregnancy (adjusted odds ratio [aOR] = 1.56; 95% confidence interval [CI]: 1.13–2.15) and in the first trimester of pregnancy (aOR = 2.24; 95%CI: 1.57–3.20) were observed an increased risk of CHD. Our study also found that polymorphisms of maternal MTHFD1 gene at rs1950902 (AA vs. GG: aOR = 1.73, 95% CI: 1.01–2.97), rs2236222 (GG vs. AA: aOR = 2.38, 95% CI: 1.38–4.12), rs1256142 (GA vs.GG: aOR = 1.57, 95% CI: 1.01–2.45) and rs11849530 (GG vs. AA: aOR = 1.68, 95% CI: 1.02–2.77) were significantly associated with higher risk of CHD. However, we did not observe a significant association between maternal MTHFD1 rs2236225 and offspring CHD risk. Furthermore, we found the different degrees of interaction effects between polymorphisms of the MTHFD1 gene including rs1950902, rs2236222, rs1256142, rs11849530 and rs2236225, and maternal tobacco exposure. Conclusions Maternal polymorphisms of MTHFD1 gene, maternal tobacco exposure and their interactions are significantly associated with the risk of CHD in offspring in Han Chinese populations. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings. Trial registration Registration number: ChiCTR1800016635.

Maternal periconceptional environmental exposure and offspring with congenital heart disease: a case–control study in Guangzhou, China

“…Similarly, Wang et al [ 35 ] found that higher parity groups showed a decreased risk of isolated CHDs. Moreover, we found that mothers who reported having a lack of folic acid use, passive smoking during pregnancy, threatened abortion, maternal history of CHD, take medicine during the first trimester, assisted reproduction, infant with preterm birth have a higher prevalence of CHDs in offspring, these findings were also consistent with previous studies which suggested that mothers with these characteristics had an increased risk of having offspring with CHDs [ 12 , 14 , 36 – 38 ]. Furthermore, maternal history of internal diseases and hyperthyroidism were positively associated with higher risk for CHDs in offspring.…”

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study

“…One study found maternal dietary factors and cystathionine beta synthase ( CBS ) gene variants (rs2851391, rs234714) interactions were significantly associated with risk of CHDs [ 51 ]. One study observed the interaction between maternal tobacco exposure and polymorphisms of the MTHFD1 gene including rs1950902, rs2236222, rs1256142, rs11849530 and rs2236225, was significantly associated with the risk of CHDs in offspring [ 52 ]. One study reported a significantly positive interaction between maternal folic acid supplementation and genetic variation at rs828858 of MTHFD2 for the risk of CHDs [ 53 ].…”

Association of Maternal Folate Intake and Offspring MTHFD1 and MTHFD2 Genes with Congenital Heart Disease

“…In this study, professionally trained investigators conducted face-to-face interviews to collect data. Based on our previous studies [ 18 , 26 ], the following covariables were used as confounding factors for subsequent analysis: socio-demographic characteristics (residence, maternal age of pregnancy, pre-pregnancy body mass index (BMI), and child sex), adverse pregnancy history (spontaneous abortion, stillbirth, premature delivery, and low birth weight (LBW)), pre-pregnancy chronic diseases (diabetes), history of pregnancy complications (gestational diabetes and gestational hypertension), and maternal perinatal lifestyle (antibiotic use, perinatal cold, fever, smoking, exposure to second-hand smoke, and drinking). In China, every pregnant woman possesses a “Perinatal Health Handbook” (PHCH), which contains her pregnancy and personal information.…”

“…Disruptions in the function of MTHFD1 and MTHFD2 genes, caused by mutations or abnormalities, can interfere with folic acid metabolism and have adverse effects on cellular biological processes [ 17 ]. Previous studies suggested that genetic variations in MTHFD1 and MTHFD2 genes may contribute to the occurrence and development of CHD [ 18 , 19 , 20 ]. Notably, a study using a mouse model observed that deficiency in MTHFD1 synthetase was associated with a higher incidence of CHD, particularly ventricular septal defects (VSD).…”

“…However, the current study only focused on the relationship between certain loci of MTHFD1 and MTHFD2 genes (G1958A/rs2236225, rs1950902, etc.) and CHD [ 18 , 22 , 23 , 24 ]. Therefore, this study aimed to comprehensively analyze the loci of MTHFD1 and MTHFD2 genes and further investigate the interaction between maternal FAS and MTHFD1 and MTHFD2 genes in relation to CHD.…”