O'Leary Valerie B, Mills James L, Parle-McDermott Anne, Pangilinan Faith, Molloy Anne M, Cox Christopher, Weiler Andrea, Conley Mary, Kirke Peadar N, Scott John M, Brody Lawrence C
Department of Biochemistry, Trinity College Dublin, Dublin, Ireland.
Am J Med Genet A. 2005 Oct 1;138A(2):99-106. doi: 10.1002/ajmg.a.30846.
The enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR) plays a key role in cellular folate metabolism. The A222V (677C->T) polymorphism is a confirmed neural tube defect (NTD) risk factor within Irish and other populations. To search for other unknown single nucleotide polymorphisms (SNPs) that might play a role in the etiology of NTDs, we examined the entire MTHFR coding region in healthy individuals (n = 100). SNPs were identified using sequencing and database analysis and allele frequencies were determined in our Irish population. We identified P39P (116C->T; T allele frequency 0.13) and previously reported R594Q (1793G->A; Q allele frequency 0.07). We screened a large ethnically homogeneous Irish NTD cohort (n>1,300) for P39P and R594Q. A possible association between NTD cases and P39P (P = 0.034) was found but this was not confirmed by transmission disequilibrium testing. R594Q also showed some evidence of a NTD case association (P = 0.07). Further analysis indicated these observations are due to linkage disequilibrium with A222V (677C->T), and therefore these new SNPs are unlikely to be independent risk factors for NTDs. As rates of NTDs differ between ethnic groups, we examined allele and genotype frequencies of P39P and R594Q within African-American and American-Caucasian populations. This is the first NTD association study of both R594Q and the novel P39P. The association with NTD risk reported for these SNPs is driven by the linkage disequilibrium with the A222V (677C->T) NTD risk factor.
5,10-亚甲基四氢叶酸还原酶（MTHFR）在细胞叶酸代谢中起关键作用。A222V（677C→T）多态性是爱尔兰及其他人群中已确认的神经管缺陷（NTD）风险因素。为了寻找可能在NTD病因中起作用的其他未知单核苷酸多态性（SNP），我们检测了100名健康个体的整个MTHFR编码区。通过测序和数据库分析鉴定SNP，并在我们的爱尔兰人群中确定等位基因频率。我们鉴定出了P39P（116C→T；T等位基因频率0.13）和先前报道的R594Q（1793G→A；Q等位基因频率0.07）。我们在一个大型种族同质的爱尔兰NTD队列（n>1300）中筛查了P39P和R594Q。发现NTD病例与P39P之间可能存在关联（P = 0.034），但传递不平衡检验未证实这一点。R594Q也显示出与NTD病例相关的一些证据（P = 0.07）。进一步分析表明，这些观察结果是由于与A222V（677C→T）的连锁不平衡所致，因此这些新的SNP不太可能是NTD的独立风险因素。由于不同种族群体中NTD的发生率不同，我们检测了非裔美国人和美国白种人群体中P39P和R594Q的等位基因和基因型频率。这是首次对R594Q和新的P39P进行的NTD关联研究。这些SNP与NTD风险的关联是由与A222V（677C→T）NTD风险因素的连锁不平衡驱动的。
