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

Xinli Song,Jingyi Diao,Tingting Wang,Yihuan Li,Jianhui Wei,Lijuan Zhao,Jinqi Li,Letao Chen,Qiongxuan Li,Peng Huang,Senmao Zhang,Yiping Liu,Jing Shu,Jiabi Qin,Mengting Sun

doi:10.1186/s12884-022-04419-2

Abstract

BackgroundMTHFD1 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.MethodsA 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.ResultsMothers 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.ConclusionsMaternal 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 registrationRegistration number: ChiCTR1800016635.

Highlights

methylenetetrahydrofolate dehydrogenase 1 (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)
These factors were adjusted when accessing the association of maternal tobacco exposure, the genetic variants of the maternal MTHFD1 gene, and their interactions with the risk of CHD in offspring
After adjustment for baseline data, mothers exposed to secondhand smoke in 3 months before pregnancy were observed an increased risk of CHD in offspring

Summary

Introduction

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). The methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene, located on chromosome 14q24, encoded the trifunctional enzyme MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase [11], 5,10-methenyltetrahydrofolate cyclohydrolase, and 10-formyltetrahydrofolate synthetase) This enzyme catalyzed three sequential reactions in the interconversion of tetrahydrofolate (THF) to 5,10-methylenetettrahydrofolate (5,10-methylene THF), the crucial substrate for 5-methyltetrahydrofolate (5-methlyTHF), which was required for DNA synthesis, DNA repair and provided the methyl donor for regeneration of methionine from homocysteine for subsequent methylation reactions [12, 13]. Previous studies focused mainly on a small number of functional nonsynonymous single-nucleotide polymorphisms (SNPs) of the MTHFD1 gene with known biochemical phenotypes such as rs1950902 and rs2236225; the other significant variants have been largely ignored; this study represents both the first report and replication efforts in Han Chinese populations

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Results

Discussion

Conclusion