Erdogan-Yildirim Zeynep, Carlson Jenna C, Mukhopadhyay Nandita, Leslie-Clarkson Elizabeth J, Padilla Carmencita D, Murray Jeffrey C, Beaty Terri H, Weinberg Seth M, Marazita Mary L, Shaffer John R
Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Genes (Basel). 2025 Jul 25;16(8):876. doi: 10.3390/genes16080876.
BACKGROUND/OBJECTIVES: Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL/P)-a common and highly heritable birth defect with a multifactorial etiology.
To identify new risk loci, we conducted a genome-wide gene-environment interaction (GEI) analysis of CL/P with maternal smoking and vitamin use in Filipinos ( = 540, = 260). Since GEI analyses are typically low in power and the results can be difficult to interpret, we applied multiple testing frameworks to evaluate potential GEI effects: a one degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach.
While no genome-wide significant interactions were detected, we identified 11 suggestive GEIs with smoking and 24 with vitamin use. Several implicated loci contain biologically plausible genes. Notable interactions with smoking include loci near , , and . While is involved in early neuronal development, and regulate epithelial-mesenchymal transition, which is required for proper lip and palate fusion. Interactions with vitamins encompass CECR2-a chromatin remodeling protein required for neural tube closure-and FURIN, a critical protease during early embryogenesis that activates various growth factors and extracellular matrix proteins. The activity of both proteins is influenced by folic acid.
Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL/P and provide new paths to explore for CL/P genetics.
背景/目的：已知母亲接触某些因素会影响单纯唇裂伴或不伴腭裂（CL/P）的风险——CL/P是一种常见且具有高度遗传性的出生缺陷，其病因是多因素的。
为了确定新的风险基因座，我们对菲律宾人（n = 540，m = 260）中CL/P与母亲吸烟及维生素使用情况进行了全基因组基因-环境相互作用（GEI）分析。由于GEI分析通常效能较低且结果难以解释，我们应用了多种检验框架来评估潜在的GEI效应：单自由度（1df）基因-环境交互作用检验、三自由度联合检验以及两步EDGE方法。
虽然未检测到全基因组显著的相互作用，但我们鉴定出11个与吸烟相关的提示性GEI以及24个与维生素使用相关的提示性GEI。几个涉及的基因座包含生物学上合理的基因。与吸烟的显著相互作用包括位于 、 和 附近的基因座。 参与早期神经元发育，而 和 调节上皮-间充质转化，这是唇和腭正常融合所必需的。与维生素的相互作用包括CECR2（神经管闭合所需的染色质重塑蛋白）和弗林蛋白酶（早期胚胎发育过程中的一种关键蛋白酶，可激活各种生长因子和细胞外基质蛋白）。这两种蛋白质的活性均受叶酸影响。
我们的研究结果突出了母亲接触某些因素在识别与CL/P等结构性出生缺陷相关基因方面的关键作用，并为探索CL/P遗传学提供了新途径。
