Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study

Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring.
A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted.
The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring.
Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

现有研究证据表明，围受孕期叶酸补充可预防先天性心脏病（Congenital Heart Disease, CHD）。甲硫氨酸合成酶还原酶（Methionine Synthase Reductase, MTRR）是叶酸代谢通路中的关键调控酶之一。本研究旨在全面评估母体MTRR基因的单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）与子代先天性心脏病发病风险的关联。
本研究采用基于医院的病例对照研究设计，共纳入740例先天性心脏病患儿母亲及683名健康对照母亲。
研究结果显示，母体MTRR基因的rs1532268位点（C/T与C/C基因型对比：调整后比值比（adjusted Odds Ratio, aOR）=1.524；T/T与C/C基因型对比：aOR=3.178）、rs1802059位点（G/A与G/G基因型对比：aOR=1.410；A/A与G/G基因型对比：aOR=3.953）、rs2287779位点（G/A与G/G基因型对比：aOR=0.540）、rs16879334位点（C/G与C/C基因型对比：aOR=0.454）及rs2303080位点（T/A与T/T基因型对比：aOR=0.546）均与子代先天性心脏病发病风险存在显著关联。此外，本研究共观测到7种单体型与子代先天性心脏病发病风险相关：其中T-G-A单体型（比值比（Odds Ratio, OR）=1.298）、C-A-C-C单体型（OR=4.824）及A-G单体型（OR=1.751）可升高子代先天性心脏病发病风险；而A-A-A（OR=0.773）、T-A-A（OR=0.557）、G-A-C-C（OR=0.598）及G-C（OR=0.740）单体型则可降低子代先天性心脏病发病风险。
综上，母体MTRR基因多态性与子代先天性心脏病发病风险显著相关，其相关单体型亦可影响先天性心脏病的发生。鉴于先天性心脏病本身具有复杂的发病机制及表型异质性，上述因素影响子代心脏发育的具体分子机制尚未明确，未来仍需在多民族大样本人群中开展进一步研究予以验证。