A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects.
A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects.
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DOI：
10.1111/ahg.12139
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发表时间：
2016-01
影响因子：
1.9
通讯作者：
Hobbs CA
中科院分区：
文献类型：
--
作者：
Li M;Li J;Wei C;Lu Q;Tang X;Erickson SW;MacLeod SL;Hobbs CA
先天性心脏病（CHD）是通过遗传变异、表观遗传修饰和母体环境暴露之间复杂的相互作用而发生的。CHD的遗传学研究通常测试单个遗传变异与CHD的关联。对复杂的基因与基因和基因与环境的相互作用的关注较少。在这项研究中，我们应用了最近开发的似然比曼-惠特尼（LRMW）方法来检测母体变异，胎儿变异和母体环境暴露之间的联合作用，允许高阶统计相互作用。所有受试者均来自国家出生缺陷预防研究，包括623对患有CHD影响的妊娠的母亲-后代和875对未受影响的妊娠的母亲-后代。每个人都有872个单核苷酸多态性，编码同型半胱氨酸、叶酸和转硫途径中的关键酶。通过使用LRMW方法，确定了三种变体（胎儿rs625879，母体rs 2169650和母体rs 8177441）与CHD风险联合相关（标称P值=1.13e-07）。这3种变体分别位于基因BHMT 2、GSTP 1和GPX 3内。进一步的研究表明，母体SNP rs 2169650可能与胎儿SNP rs625879和母体SNP rs 8177441相互作用。我们的研究结果表明，CHD的风险可能受到母体基因组内的代内相互作用以及母体和胎儿基因组之间的代间相互作用的影响。
Congenital heart defects (CHDs) develop through a complex interplay between genetic variants, epigenetic modifications and maternal environmental exposures. Genetic studies of CHDs have commonly tested single genetic variants for association with CHDs. Less attention has been given to complex gene-by-gene and gene-by-environment interactions. In this study, we applied a recently developed likelihood-ratio Mann-Whitney (LRMW) method to detect joint actions among maternal variants, fetal variants and maternal environmental exposures, allowing for high-order statistical interactions. All subjects are participants from the National Birth Defect Prevention Study, including 623 mother-offspring pairs with CHD-affected pregnancies and 875 mother-offspring pairs with unaffected pregnancies. Each individual has 872 single nucleotide polymorphisms encoding for critical enzymes in the homocysteine, folate, and transsulfuration pathways. By using the LRMW method, three variants (fetal rs625879, maternal rs2169650 and maternal rs8177441) were identified with a joint association to CHD risk (nominal P-value=1.13e-07). These 3 variants are located within gene BHMT2, GSTP1 and GPX3, respectively. Further examination indicated that maternal SNP rs2169650 may interact with both fetal SNP rs625879 and maternal SNP rs8177441. Our findings suggest that the risk of CHD may be influenced by both the intra-generational interaction within the maternal genome and the inter-generational interaction between maternal and fetal genomes.