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Title: Association of periconceptional folate supplements and FOLR1 and FOLR2 gene polymorphisms with risk of congenital heart disease in offspring: A hospital-based case-control study.
Author: Song X, Huang P, Wang T, Zhang S, Chen L, Qin J.
Journal: Zhong Nan Da Xue Xue Bao Yi Xue Ban; 2022 Jan 28; 47(1):52-62. PubMed ID: 35545363.
Abstract:
OBJECTIVES: Maternal periconceptional folic acid supplement is by far the most effective primary prevention strategy to reduce the incidence of congenital heart disease (CHD) in offspring. It was revealed that the underlying mechanisms are complex, including a combination of genetic and environmental factors. The purpose of this study is to investigate the association between periconceptional folic acid supplement, the genetic polymorphisms of maternal folic acid receptor 1 gene (FOLR1) and folic acid receptor 2 gene (FOLR2) and the impact of their interaction on the risk of CHD in offspring, and to provide epidemiological evidence for individualized folic acid dosing in hygienic counseling. METHODS: A case-control study on 569 mothers of CHD infants and 652 mothers of health controls was performed. The interesting points were periconceptional folate supplements, single nucleotide polymorphisms (SNPs) of maternal FOLR1 gene and FOLR2 gene. RESULTS: Mothers who took folate in the periconceptional period were observed a decreased risk of CHD [adjusted odds ratio (aOR)=0.58, 95% CI 0.35 to 0.95]. Our study also found that polymorphisms of maternal FOLR1 gene at rs2071010 (G/A vs G/G: aOR=0.67, 95% CI 0.47 to 0.96) and FOLR2 gene at rs514933 (T/C vs T/T: aOR=0.60, 95% CI 0.43 to 0.84; C/C vs T/T: aOR=0.55, 95% CI 0.33 to 0.90; the dominant model: T/C+ C/C vs T/T: aOR=0.59, 95% CI 0.43 to 0.81; and the addictive model: C/C vs T/C vs T/T: aOR=0.70, 95% CI 0.56 to 0.88) were significantly associated with lower risk of CHD [all P<0.05, false discovery rate P value (FDR_P)<0.1]. Besides, significant interaction between periconceptional folate supplements and rs2071010 G→A (aOR=0.59, 95% CI 0.41-0.86) and rs514933 T→C (aOR=0.52, 95% CI 0.37 to 0.74) on CHD risk were observed (all P<0.05, FDR_P<0.1). CONCLUSIONS: Periconceptional folate supplements, polymorphisms of FOLR1 gene and FOLR2 gene and their interactions are significantly associated with risk of CHD. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings. 目的: 母亲围孕期服用叶酸是迄今为止减少子代先天性心脏病(congenital heart disease，CHD)最有效的一级预防措施，既往研究提示其相关机制涉及基因和环境因素，但仍未阐明。本研究旨在探讨母亲围孕期服用叶酸、叶酸受体1基因(FOLR1)和叶酸受体2基因(FOLR2)多态性及两者的交互作用与子代CHD的关系，以期为围孕期叶酸服用剂量的个体化指导提供流行病学证据。方法: 采用医院为基础的病例对照研究，招募2017年12月至2020年3月在湖南省儿童医院确诊的569例单纯性CHD患儿的母亲为病例组，以同期、该院确诊的无先天性疾病的652例正常儿的母亲为对照组。通过以问卷为基础的面对面访谈，收集母亲人口学信息和围孕期相关暴露信息，同时采集母亲静脉血 5 mL用于FOLR1和FOLR2基因多态性检测。采用多因素logistic回归分析探讨母亲围孕期服用叶酸、FOLR1和FOLR2基因多态性及两者交互作用与子代CHD的关联性。结果: 多因素logistic回归分析显示：调整混杂因素后，围孕期服用叶酸能够显著降低子代CHD的风险[调整的相对危险比(adjusted odds ratio，aOR)=0.58，95% CI：0.35~0.95]。母亲FOLR1基因位点rs2071010(G/A vs G/G：aOR=0.67，95% CI：0.47~0.96)与子代CHD风险显著相关[P<0.05，错误发现率P值(false discovery rate P value，FDR_P)<0.1]；FOLR2基因位点rs514933(T/C vs T/T：aOR=0.60，95% CI：0.43~0.84；C/C vs T/T：aOR=0.55，95% CI：0.33~0.90)在显性模型[(T/C+C/C) vs T/T：aOR=0.59，95% CI：0.43~0.81]和加性模型(C/C vs T/C vs T/T：aOR=0.70，95% CI：0.56~0.88)下均与子代CHD风险显著相关(均P<0.05，FDR_P<0.1)。rs2071010 G→A(aOR=0.59，95% CI：0.41~0.86)和rs514933 T→C(aOR=0.52，95% CI：0.37~0.74)与母亲围孕期服用叶酸在子代CHD发生中存在交互作用(P<0.05，FDR_P<0.1)。结论: 母亲携带FOLR1基因rs2071010 G→A与FOLR2基因rs514933 T→C的突变型能够降低子代CHD的发生风险，且围孕期服用叶酸可以强化SNP rs2071010和SNP rs514933对子代发生CHD的保护作用。. OBJECTIVE: Maternal periconceptional folic acid supplement is by far the most effective primary prevention strategy to reduce the incidence of congenital heart disease (CHD) in offspring. It was revealed that the underlying mechanisms are complex, including a combination of genetic and environmental factors. The purpose of this study is to investigate the association between periconceptional folic acid supplement, the genetic polymorphisms of maternal folic acid receptor 1 gene (FOLR1) and folic acid receptor 2 gene (FOLR2) and the impact of their interaction on the risk of CHD in offspring, and to provide epidemiological evidence for individualized folic acid dosing in hygienic counseling. METHODS: A case-control study on 569 mothers of CHD infants and 652 mothers of health controls was performed. The interesting points were periconceptional folate supplements, single nucleotide polymorphisms (SNPs) of maternal FOLR1 gene and FOLR2 gene. RESULTS: Mothers who took folate in the periconceptional period were observed a decreased risk of CHD [adjusted odds ratio (aOR)=0.58, 95% CI 0.35 to 0.95]. Our study also found that polymorphisms of maternal FOLR1 gene at rs2071010 (G/A vs G/G: aOR=0.67, 95% CI 0.47 to 0.96) and FOLR2 gene at rs514933 (T/C vs T/T: aOR=0.60, 95% CI 0.43 to 0.84; C/C vs T/T: aOR=0.55, 95% CI 0.33 to 0.90; the dominant model: T/C+ C/C vs T/T: aOR=0.59, 95% CI 0.43 to 0.81; and the addictive model: C/C vs T/C vs T/T: aOR=0.70, 95% CI 0.56 to 0.88) were significantly associated with lower risk of CHD [all P<0.05, false discovery rate P value (FDR_P)<0.1]. Besides, significant interaction between periconceptional folate supplements and rs2071010 G→A (aOR=0.59, 95% CI 0.41-0.86) and rs514933 T→C (aOR=0.52, 95% CI 0.37 to 0.74) on CHD risk were observed (all P<0.05, FDR_P<0.1). CONCLUSION: Periconceptional folate supplements, polymorphisms of FOLR1 gene and FOLR2 gene and their interactions are significantly associated with risk of CHD. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings.

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