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 (<i>MTRR</i>) 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 <i>MTRR</i> 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 <i>MTRR</i> gene polymorphisms at rs1532268 (C/T <i>vs.</i> C/C: aOR = 1.524; T/T <i>vs.</i> C/C: aOR = 3.178), rs1802059 (G/A <i>vs.</i> G/G: aOR = 1.410; A/A <i>vs.</i> G/G: aOR = 3.953), rs2287779 (G/A <i>vs.</i> G/G: aOR = 0.540), rs16879334 (C/G <i>vs.</i> C/C: aOR = 0.454), and rs2303080 (T/A <i>vs.</i> 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 <i>MTRR</i> 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.

现有证据表明，围孕期叶酸补充可预防先天性心脏病（congenital heart disease, CHD）。甲硫氨酸合酶还原酶（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。本研究开展了一项基于医院的病例对照研究，共纳入740例先天性心脏病患儿母亲及683名健康对照。研究显示，母体MTRR基因的rs1532268位点（C/T vs C/C：调整后比值比adjusted odds ratio, aOR=1.524；T/T vs C/C：aOR=3.178）、rs1802059位点（G/A vs G/G：aOR=1.410；A/A vs G/G：aOR=3.953）、rs2287779位点（G/A vs G/G：aOR=0.540）、rs16879334位点（C/G vs C/C：aOR=0.454）及rs2303080位点（T/A vs T/T：aOR=0.546）均与子代先天性心脏病风险存在关联。共观察到7种单倍型与子代先天性心脏病风险相关：其中T-G-A单倍型（比值比odds ratio, OR=1.298）、C-A-C-C单倍型（OR=4.824）及A-G单倍型（OR=1.751）会增加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）单倍型则会降低子代先天性心脏病发病风险。母体MTRR基因多态性与子代先天性心脏病相关，其单倍型亦会影响先天性心脏病的发生。此外，鉴于先天性心脏病的复杂性与异质性，上述因素影响子代心脏发育的具体机制仍不明确，未来需在种族多样化人群中开展更大样本量的研究加以验证。