Institute of Reproductive and Child Health, NHC Key Laboratory of Reproductive Health, Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
Birth Defects Res. 2019 Nov 15;111(19):1468-1478. doi: 10.1002/bdr2.1556. Epub 2019 Jul 22.
Neural tube defects (NTDs) are the most common severe birth defects with complex etiologies. Previous studies conducted on animals have suggested that the Grhl3 gene is essential for closure of the spinal neural tube, but little evidence from human studies on the variants of GRHL3 gene has been provided, especially the common genetic variants.
To investigate the relationship between common genetic variants of GRHL3 and the risk for NTDs, we performed a case-control study and a case-parent triad/control study. Fast-target enrichment sequencing was performed to screen exon regions from 503 NTD cases, and three tag SNPs (single nucleotide polymorphisms, including rs12030057, rs2486668, and rs545809) were selected according to the sequencing results. Then, Sequenom MassARRAY genotyping was performed in 757 case parents and 519 controls to obtain genotype information of the target variant sites among all NTD triads and controls.
The genotype distributions of all SNPs were in accordance with Hardy-Weinberg Equilibrium (HWE) in the control population. In the case-control study, significant associations were found between C27G genetic variants on rs2486668 and risk for spina bifida and encephalocele, respectively, under different genetic models. Consistently, in the case-parent triad/control study, GG genotype on rs2486668 was associated with increased risk for spina bifida, with a RR of 2.15 (95% CI: 1.20-3.83). However, no parent-of-origin effect was found for any tag SNPs.
The GRHL3 C67G missense variant may increase the risk for spina bifida and encephalocele phenotypes.
神经管缺陷（NTDs）是最常见的严重出生缺陷，具有复杂的病因。先前在动物身上进行的研究表明，Grhl3 基因对于脊髓神经管的闭合至关重要，但人类研究提供的关于 GRHL3 基因变异的证据很少，特别是常见的遗传变异。
为了研究 GRHL3 常见遗传变异与 NTD 风险之间的关系，我们进行了病例对照研究和病例-父母三/对照研究。采用快速靶向富集测序筛选 503 例 NTD 病例的外显子区域，根据测序结果选择 3 个标签 SNP（单核苷酸多态性，包括 rs12030057、rs2486668 和 rs545809）。然后，在 757 例病例父母和 519 例对照中进行 Sequenom MassARRAY 基因分型，以获得所有 NTD 三/对照中目标变异位点的基因型信息。
所有 SNP 的基因型分布在对照人群中均符合 Hardy-Weinberg 平衡（HWE）。在病例对照研究中，在不同遗传模型下，rs2486668 的 C27G 遗传变异与脊柱裂和脑膨出的风险分别存在显著关联。一致地，在病例-父母三/对照研究中，rs2486668 的 GG 基因型与脊柱裂的风险增加相关，RR 为 2.15（95%CI：1.20-3.83）。然而，没有发现任何标签 SNP 存在亲代来源效应。
GRHL3 C67G 错义变异可能增加脊柱裂和脑膨出表型的风险。
