Li Ming, Li Jingyun, Wei Changshuai, Lu Qing, Tang Xinyu, Erickson Stephen W, MacLeod Stewart L, Hobbs Charlotte A
Department of Epidemiology and Biostatistics, Indiana University at Bloomington, Bloomington, IN, USA.
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Ann Hum Genet. 2016 Jan;80(1):20-31. doi: 10.1111/ahg.12139. Epub 2015 Nov 27.
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 trans-sulfuration 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 three variants are located within genes 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 intragenerational interaction within the maternal genome and the intergenerational interaction between maternal and fetal genomes.
先天性心脏病（CHD）是通过基因变异、表观遗传修饰和母体环境暴露之间复杂的相互作用而形成的。CHD的基因研究通常测试单个基因变异与CHD的关联。而对复杂的基因-基因和基因-环境相互作用的关注较少。在本研究中，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，同时考虑高阶统计相互作用。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的母婴对和875对未受影响的母婴对。每个个体有872个单核苷酸多态性，这些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，确定了三个变异（胎儿rs625879、母体rs2169650和母体rs8177441）与CHD风险存在联合关联（名义P值 = 1.13e-07）。这三个变异分别位于BHMT2、GSTP1和GPX3基因内。进一步检查表明，母体单核苷酸多态性rs2169650可能与胎儿单核苷酸多态性rs625879和母体单核苷酸多态性rs8177441都存在相互作用。我们的研究结果表明，CHD的风险可能受到母体基因组内代内相互作用以及母体和胎儿基因组之间代际相互作用的影响。
