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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12884-022-04419-2.