Association of methylenetetrahydrofolate reductase gene polymorphisms and maternal folic acid use with the risk of congenital heart disease

Abstract

BackgroundTo systematically evaluate the association of MTHFR genetic polymorphisms, maternal folic acid intake, and the time when folic acid intake was started with the risk of congenital heart disease (CHD) and investigated the role of their interaction on infant CHD risk in Chinese populations.MethodsA case–control study involving 592 CHD cases, 617 health controls, and their mothers was performed. The exposures of interest were single nucleotide polymorphisms (SNPs) of the MTHFR gene, maternal folic acid use, and the time when folic acid use was started. We applied the logistic regression model to explore the strength of association.ResultsOur findings showed that mothers lacking folic acid intake had a significantly higher risk of CHD in offspring (aOR = 2.00; 95%CI: 1.34–2.98). Mothers who started to use folic acid from the first trimester of the fetation (aOR = 1.65; 95% CI: 1.22–2.23) or from the second trimester of the fetation (aOR = 7.77; 95% CI: 2.52–23.96), compared with those starting to use folic acid from 3 months previous to the conception, were at a significantly higher risk of CHD in offspring. Genetic variants at rs2066470 (AA vs. GG: aOR = 5.09, 95%CI: 1.99–13.03), rs1801133 (AA vs. GG: aOR = 2.49, 95%CI: 1.58–3.93), and rs1801131 (TG vs. TT: aOR = 1.84, 95%CI: 1.36–2.50; GG vs. TT: aOR = 3.58, 95%CI: 1.68–7.63) were significantly associated with the risk of CHD based on the multivariate analysis. Additionally, statistically significant interactions between maternal folic acid intake and genetic variants of the MTHFR gene at rs1801133 and rs1801131 were observed.ConclusionAn association of maternal folic acid intake and the time when intake was started with the risk of CHD in offspring was found. What's more, maternal folic acid fortification may help counteract partial of the risks of CHD in offspring attributable to MTHFR genetic mutations.Registration numberhttp://www.chictr.org.cn/edit.aspx?pid=28300&htm=4, identifier: ChiCTR1800016635.

Association of Maternal Dietary Habits and Infant MTHFR Gene Polymorphisms with Ventricular Septal Defect in Offspring: A Case–Control Study

“…Our research team has priorly demonstrated the associations of maternal MTHFR rs1801131 polymorphisms with CHD (OR = 5.18) and VSD subtype (OR = 4.98), while no such correlation was observed for rs1801133 with target diseases [11]. Moreover, our published article indicated that infant MTHFR gene polymorphisms increased the risk of CHD (rs2066470: OR = 5.09; rs1801133: OR = 2.49; rs1801131: OR = 1.84) [12]. In the present study, we further explored the SNPs of the infant MTHFR gene, maternal dietary habits, and the impact of gene-environment interactions on VSD, the predominant phenotype of cardiac defects.…”

“…Polymorphisms of the MTHFR gene result in impaired enzyme activity and disturbed clearance of homocysteine and subsequently present with hyperhomocysteinemia, the acknowledged teratogen and risk factor of CHD, presumably due to oxidative stress [17][18][19]. Epidemiological evidence has documented associations between maternal and infant MTHFR gene polymorphisms at rs1801133 and rs1801131 and CHD [12,14,20]. The current study focuses on the relationship between offspring MTHFR gene polymorphisms and VSDs, the major subtype of CHD, and this investigation extends beyond the two loci mentioned above.…”

“…Previous studies have pointed out that polymorphisms of genes implicated in the folate-homocysteine pathway were associated with the occurrence of CHD, encompassing methylenetetrahydrofolate reductase (MTHFR) [11,12], cysteine acetylase (CBS) [13], methionine synthase (MTR) [14], and methionine synthase reductase (MTRR) [15]. The prevailing MTHFR gene encodes the essential enzyme involved in the one-carbon pathway, converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.…”

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.…”