Pangilinan Faith, Geiler Kerry, Dolle Jessica, Troendle James, Swanson Deborah A, Molloy Anne M, Sutton Marie, Conley Mary, Kirke Peadar N, Scott John M, Mills James L, Brody Lawrence C
Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892-8004, USA.
Am J Med Genet A. 2008 Oct 15;146A(20):2617-25. doi: 10.1002/ajmg.a.32504.
Genetic and environmental factors contribute to the etiology of neural tube defects (NTDs). While periconceptional folic acid supplementation is known to significantly reduce the risk of NTDs, folate metabolic pathway related factors do not account for all NTDs. Evidence from mouse models indicates that the tumor protein p53 (TP53) is involved in implantation and normal neural tube development. To determine whether genetic variation in TP53 might contribute to NTD risk in humans, we constructed a high resolution linkage disequilibrium (LD) map of the TP53 genomic region based on genotyping 21 markers in an Irish population. We found that nine of these variants can be used to capture the majority of common variation in the TP53 genomic region. In contrast, the 3-marker haplotype commonly reported in the TP53 literature offers limited coverage of the variation in the gene. We used the expanded set of polymorphisms to measure the influence of TP53 on NTDs using both case-control and family based tests of association. We also assayed a functional variant in the p53 regulator MDM2 (rs2279744). Alleles of three noncoding TP53 markers were associated with NTD risk. A case effect was seen with the GG genotype of rs1625895 in intron 6 (OR = 1.37 [1.04-1.79], P = 0.02). A maternal effect was seen with the 135/135 genotype of the intron 1 VNTR (OR = 1.86 [1.16-2.96], P = 0.01) and the TT genotype of rs1614984 (RR = 0.58 [0.37-0.91], P = 0.02). As multiple comparisons were made, these cannot be considered definitive positive findings and additional investigation is required.
遗传和环境因素都对神经管缺陷（NTDs）的病因有影响。虽然已知孕前补充叶酸可显著降低神经管缺陷的风险，但叶酸代谢途径相关因素并不能解释所有的神经管缺陷病例。小鼠模型的证据表明，肿瘤蛋白p53（TP53）参与着床和正常神经管发育。为了确定TP53基因变异是否会增加人类患神经管缺陷的风险，我们在爱尔兰人群中对21个标记进行基因分型，构建了TP53基因区域的高分辨率连锁不平衡（LD）图谱。我们发现其中9个变异可用于捕获TP53基因区域的大部分常见变异。相比之下，TP53文献中通常报道的3标记单倍型对该基因变异的覆盖范围有限。我们使用扩展的多态性集合，通过病例对照和基于家系的关联测试来测量TP53对神经管缺陷的影响。我们还检测了p53调节因子MDM2中的一个功能性变异（rs2279744）。三个非编码TP53标记的等位基因与神经管缺陷风险相关。内含子6中rs1625895的GG基因型有病例效应（OR = 1.37 [1.04 - 1.79]，P = 0.02）。内含子1可变数目串联重复序列（VNTR）的135/135基因型和rs1614984的TT基因型有母体效应（OR = 1.86 [1.16 - 2.96]，P = 0.01；RR = 0.58 [0.37 - 0.91]，P = 0.02）。由于进行了多次比较，这些不能被视为确定性的阳性发现，还需要进一步研究。
