Kase Benjamin A, Northrup Hope, Morrison Alanna C, Davidson Christina M, Goiffon Amanda M, Fletcher Jack M, Ostermaier Kathryn K, Tyerman Gayle H, Au Kit Sing
Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
Birth Defects Res A Clin Mol Teratol. 2012 Oct;94(10):762-9. doi: 10.1002/bdra.23065. Epub 2012 Sep 13.
A common and severe neural tube defect (NTD) phenotype, myelomeningocele (MM), results from the defective closure of the caudal end of the neural tube with herniation of the spinal cord and meninges through the vertebral column. The exact mechanisms for NTDs are unknown, but excessive oxidative stress, particularly in association with maternal diabetes, has been postulated as a mechanism for MM.
The SNPlex Genotyping (ABI, Foster City, CA) platform was used to investigate single nucleotide polymorphisms (SNPs) across the superoxide dismutase (SOD) 1 and 2 genes to assess their association with MM risk. The study population included 329 trio (affected child and both parents) and 281 duo (affected child and one parent) families. Only cases with documented MM were studied. Seventeen SNPs across the SOD1 and SOD2 genes met the quality-control criteria to be considered for statistical analysis. Genetic association was assessed using the family-based transmission disequilibrium test in PLINK (a genome association analysis toolset).
Four SNPs in the SOD1 gene (rs 202446, rs202447, rs4816405, and rs2070424) and one SNP in the SOD2 gene ( rs5746105) [corrected] appeared to be associated with MM risk in our population. After adjusting for multiple testing, these SNPs remained significant.
This study provides the first genetic evidence to support association of myelomeningocele with superoxide scavenging. The rare alleles of the five specific SNPs within SOD1 and SOD2 appear to confer a protective effect on the susceptibility for MM risk in the MM population tested. Further evaluation of the roles of superoxide scavenging and neural tube development is warranted.
脊髓脊膜膨出（MM）是一种常见且严重的神经管缺陷（NTD）表型，它是由于神经管尾端闭合缺陷，脊髓和脑膜通过脊柱疝出所致。NTD的确切机制尚不清楚，但过量的氧化应激，尤其是与母体糖尿病相关的氧化应激，被认为是MM的一种发病机制。
采用SNPlex基因分型（ABI，加利福尼亚州福斯特城）平台，研究超氧化物歧化酶（SOD）1和2基因的单核苷酸多态性（SNP），以评估它们与MM风险的关联。研究人群包括329个三联体家庭（患病儿童及其父母双方）和281个二联体家庭（患病儿童及其父母一方）。仅对有记录的MM病例进行研究。SOD1和SOD2基因的17个SNP符合质量控制标准，可用于统计分析。使用PLINK（一种基因组关联分析工具集）中的基于家系的传递不平衡检验评估基因关联。
SOD1基因中的4个SNP（rs 202446、rs202447、rs4816405和rs20704）和SOD2基因中的1个SNP（rs5746105）[校正后]似乎与我们研究人群中的MM风险相关。在进行多重检验校正后，这些SNP仍然具有显著性。
本研究提供了首个遗传学证据，支持脊髓脊膜膨出与超氧化物清除之间的关联。在受试的MM人群中，SOD1和SOD2内5个特定SNP的罕见等位基因似乎对MM风险易感性具有保护作用。有必要进一步评估超氧化物清除和神经管发育的作用。
