Association analysis of maternal MTHFR gene polymorphisms and the occurrence of congenital heart disease in offspring

Mengting Sun,Jinqi Li,Yihuan Li,Tingting Wang,Letao Chen,Xinli Song,Jianhui Wei,Senmao Zhang,Peng Huang,Yiping Liu,Jingyi Diao,Xiaoqi Sheng,Liu Luo,Jiabi Qin

doi:10.1186/s12872-021-02117-z

Abstract

BackgroundAlthough many studies showed that the risk of congenital heart disease (CHD) was closely related to genetic factors, the exact pathogenesis is still unknown. Our study aimed to comprehensively assess the association of single nucleotide polymorphisms (SNPs) of maternal MTHFR gene with risk of CHD and its three subtypes in offspring.MethodsA case–control study involving 569 mothers of CHD cases and 652 health controls was conducted. Thirteen SNPs were detected and analyzed.ResultsOur study showed that genetic polymorphisms of maternal MTHFR gene at rs4846052 and rs1801131 were significantly associated with risk of CHD in the homozygote comparisons (TT vs. CC at rs4846052: OR = 7.62 [95%CI 2.95–19.65]; GG vs. TT at rs1801131: OR = 5.18 [95%CI 2.77–9.71]). And six haplotypes of G–C (involving rs4846048 and rs2274976), A–C (involving rs1801133 and rs4846052), G–T (involving rs1801133 and rs4846052), G–T–G (involving rs2066470, rs3737964 and rs535107), A–C–G (involving rs2066470, rs3737964 and rs535107) and G–C–G (involving rs2066470, rs3737964 and rs535107) were identified to be significantly associated with risk of CHD. Additionally, we observed that a two-locus model involving rs2066470 and rs1801131 as well as a three-locus model involving rs227497, rs1801133 and rs1801131 were significantly associated with risk of CHD in the gene–gene interaction analyses. For three subtypes including atrial septal defect, ventricular septal defect and patent ductus arteriosus, similar results were observed.ConclusionsOur study indicated genetic polymorphisms of maternal MTHFR gene were significantly associated with risk of fetal CHD in the Chinese population. Additionally, there were significantly interactions among different SNPs on risk of CHD. However, how these SNPs affect the development of fetal heart remains unknown, and more studies in different ethnic populations and with a larger sample are required to confirm these findings.

Highlights

Congenital heart disease (CHD) is the most common birth defect, with an estimated prevalence rate of 8.6–10.3 per 1000 live births and rising [1, 2]
These factors were adjusted when assessing the association of maternal methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and their interactions with the risk of congenital heart disease (CHD) in offspring
After adjustment for potential confounding factors, our study suggested that genetic polymorphisms of maternal MTHFR gene at rs4846052 and rs1801131 were significantly associated with the susceptibility of CHD in offspring

Summary

Introduction

Congenital heart disease (CHD) is the most common birth defect, with an estimated prevalence rate of 8.6–10.3 per 1000 live births and rising [1, 2]. It is widely believed that CHD is a multifactorial disease involving environmental and genetic factors [6,7,8]. Some epidemiological evidence showed that one-third of CHD cases can be explained by genetic factors [9]. The etiology of CHD involves the gene–gene and gene-environment interactions, indicating its complexity [10,11,12]. Many studies showed that the risk of congenital heart disease (CHD) was closely related to genetic factors, the exact pathogenesis is still unknown. Our study aimed to comprehensively assess the association of single nucleotide polymorphisms (SNPs) of maternal MTHFR gene with risk of CHD and its three subtypes in offspring

Methods

Results

Discussion

Conclusion