Meng Jingjing, Han Lei, Zhuang Bo
Neonatal Ward, Jining No. 1 People's Hospital, Jining 272011, China.
Department of PICU, The Affiliated Hospital of Jining Medical College, Jining 272000, China.
J Neurol Sci. 2015 Jan 15;348(1-2):188-94. doi: 10.1016/j.jns.2014.12.001. Epub 2014 Dec 6.
Neural tube defect (NTD) is a common disease among neonates with multiplex symptom and complex origins, and the exact mechanism of NTD has not been definitely elucidated. Nevertheless, it is hypothesized that NTD risk can be prevented by periconceptional folic acid in folate metabolism. The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene has been proved to play an important role in folate metabolism, which was strongly associated with the high risk for NTD. We focused on three folate metabolism-related single-nucleotide polymorphisms (SNPs) on the MTHFD1 gene to evaluate the associations between MTHFD1 polymorphisms and NTD susceptibility.
We genotyped blood samples from 222 specimens (including 122 NTD-affected infants and 100 healthy controls) in a case-control study. We investigated the association between NTD and three selected tag-SNPs on MTHFD1 gene: 401A>G (rs1950902), 2305C>T (rs17857382) and 1958G>A (rs2236225) by the SNapShot method. These SNPs were identified by Haploview 4.2 software with HapMap databases, and then these associations were evaluated by the Mann-Whitney test, one-way analysis of variance (ANOVA) and chi-square test. Furthermore, a meta-analysis of the association between MTHFD1 1958G>A and NTD risk was also performed.
In our study, an increased risk of NTD was observed for 1958G>A of MTHFD1 (AA vs. GG: OR=2.63, 95% CI=2.61-5.70; AA vs. GG+GA: OR=2.10, 95% CI=1.07-4.14; A vs. G: OR=1.62, 95% CI=1.11-2.36). However, the other two SNPs (401A>G and 2305C>T) displayed no statistically significant association with NTD risk. The overall result of the meta-analysis indicated that the 1958G>A variant might not be a genetic susceptible factor for the Caucasian population.
Our analysis implicated that MTHFD1 1958G>A was significantly associated with the susceptibility of NTD in a Chinese population. In addition, the AA homozygote carriers were more likely to suffer NTD, compared with the others with GA or GG genotypes. Validation of the risk effect and functional impact of this polymorphism is needed in future investigations.
神经管缺陷（NTD）是新生儿中一种常见疾病，症状多样且病因复杂，NTD的确切发病机制尚未完全阐明。然而，据推测，围孕期叶酸在叶酸代谢中可预防NTD风险。亚甲基四氢叶酸脱氢酶（MTHFD1）基因已被证明在叶酸代谢中起重要作用，与NTD高风险密切相关。我们聚焦于MTHFD1基因上三个与叶酸代谢相关的单核苷酸多态性（SNP），以评估MTHFD1基因多态性与NTD易感性之间的关联。
在一项病例对照研究中，我们对222份样本（包括122例NTD患儿和100例健康对照）的血样进行基因分型。我们采用SNapShot方法研究NTD与MTHFD1基因上三个选定的标签SNP：401A>G（rs1950902）、2305C>T（rs17857382）和1958G>A（rs2236225）之间的关联。这些SNP通过Haploview 4.2软件和HapMap数据库进行识别，然后通过曼-惠特尼检验、单因素方差分析（ANOVA）和卡方检验评估这些关联。此外，还对MTHFD1基因1958G>A与NTD风险之间的关联进行了荟萃分析。
在我们的研究中，观察到MTHFD1基因1958G>A位点NTD风险增加（AA与GG比较：OR = 2.63，95%CI = 2.61 - 5.70；AA与GG + GA比较：OR = 2.10，95%CI = 1.07 - 4.14；A与G比较：OR = 1.62，95%CI = 1.11 - 2.36）。然而，其他两个SNP（401A>G和2305C>T）与NTD风险无统计学显著关联。荟萃分析的总体结果表明，1958G>A变异可能不是白种人群的遗传易感因素。
我们的分析表明，MTHFD1基因1958G>A在中国人群中与NTD易感性显著相关。此外，与GA或GG基因型的其他人相比，AA纯合子携带者更易患NTD。未来研究需要验证这种多态性的风险效应和功能影响。
