Hobbs Charlotte A, Cleves Mario A, Macleod Stewart L, Erickson Stephen W, Tang Xinyu, Li Jingyun, Li Ming, Nick Todd, Malik Sadia
Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas.
Birth Defects Res A Clin Mol Teratol. 2014 Feb;100(2):116-26. doi: 10.1002/bdra.23225. Epub 2014 Feb 18.
We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs
Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs
Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation.
These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.
我们研究了圆锥动脉干心脏缺陷（CTD）与叶酸、同型半胱氨酸和转硫途径中60个基因的母体及胎儿单核苷酸多态性（SNP）之间的关联。我们还研究了受孕前母体补充叶酸是否会改变CTD与SNP之间的关联。
参与者于1997年至2008年期间参加了国家出生缺陷预防研究。使用Illumina® Golden Gate定制SNP芯片对616例受CTD影响的病例-亲代三联体和1645例对照-亲代三联体的DNA样本进行基因分型。采用混合设计分析，优化病例和对照三联体的数据，以识别与CTD相关的母体和胎儿SNP。
在921个SNP中，17个母体SNP和17个胎儿SNP的贝叶斯错误发现概率<0.8。17个母体SNP中的10个和17个胎儿SNP中的2个位于谷氨酸-半胱氨酸连接酶催化亚基（GCLC）基因内。贝叶斯错误发现概率最低的胎儿SNP（rs2612101、rs2847607、rs2847326、rs2847324）位于胸苷酸合成酶（TYMS）基因内。进一步分析表明，受孕前补充叶酸可改变与候选SNP相关的CTD风险。19个母体SNP和9个胎儿SNP在与母体叶酸补充的基因-环境（G×E）相互作用中的贝叶斯错误发现概率<0.8。
这些结果支持了先前的研究，表明叶酸、同型半胱氨酸和转硫途径中的母体和胎儿SNP与CTD风险相关。母体使用含叶酸的补充剂可能会改变SNP对发育中心脏的影响。
