The GLI2 Missense Variant rs3738880 Significantly Increases the Risk of Neural Tube Defects in the Han Chinese Population
The GLI2 Missense Variant rs3738880 Significantly Increases the Risk of Neural Tube Defects in the Han Chinese Population
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GLI2错义变异体rs3738880显着增加中国汉族人群神经管缺陷的风险
DOI：
10.4103/2096-2924.224214
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发表时间：
2017-07
影响因子：
0.8
通讯作者：
Xueyan Yang
中科院分区：
文献类型：
--
作者：
Shuxia Chen;Hui-Li Li;Cai-Hua Li;Ting Zhang;Hongyan Wang;Xueyan Yang
背景：Sonic hedgehog(SHH)通路是神经管闭合的重要信号通路。Gli家族锌指2(GLI2)是SHH途径的主要激活介质，但目前还没有GLI2的单核苷酸多态(SNPs)与人类神经管缺陷(NTDS)相关的报道。在这里，我们评估了中国汉族人群中GLI2的突变。方法：利用SNPcan对GLI2编码区的rs3738880进行基因分型。然后，我们通过Western blotting和双荧光素酶分析研究了该基因的功能。结果：在本研究中，我们通过关联研究发现GLI2错义突变rs3738880显著增加了中国汉族人NTDS的风险(OR=1.89，95%可信区间[CI]=1.28~2.80，P=0.0012)。进一步的分层分析显示rs3738880与脊柱裂显著相关(OR=2.01，95%CI=1.19~3.38，P=0.0067)。功能分析表明，rs3738880不影响GLI2蛋白的稳定性，并且由于在GLI2中引入了一个潜在的磷酸化位点而显著增加了SHH活性。结论：rs3738880是汉族人NTDS的危险因素。
Background: The sonic hedgehog (SHH) pathway is an important signaling pathway for neural tube closure. GLI family zinc finger 2 (GLI2) is the major activation mediator of the SHH pathway; however, no single-nucleotide polymorphisms (SNPs) in GLI2 have been reported to be associated with human neural tube defects (NTDs) to date. Here, we evaluated a mutation in GLI2 in the Han Chinese population. Methods: We used SNPscan to genotype rs3738880 in the GLI2 coding region. We then investigated the function of this gene by Western blotting and dual-luciferase assays. Results: In this study, we found that the GLI2 missense variant rs3738880 significantly increased the risk of NTDs in the Han Chinese population via association studies in a cohort of 254 patients and 277 controls from Shanxi Province (odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.28–2.80, P = 0.0012). Additional stratified analyses demonstrated that rs3738880 was significantly related to spina bifida (114 cases, OR = 2.01, 95% CI = 1.19–3.38, P = 0.0067). Functional analysis revealed that rs3738880 did not affect GLI2 protein stability and significantly increased SHH activity because of the introduction of a potential phosphorylation site in GLI2. Conclusion: rs3738880 was a risk factor for NTDs in the Han Chinese population.