The GLI2 Missense Variant rs3738880 Significantly Increases the Risk of Neural Tube Defects in the Han Chinese Population

Abstract

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.