Shaw Gary M, Yang Wei, Perloff Spencer, Shaw Nathan M, Carmichael Suzan L, Zhu Huiping, Lammer Edward J
Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Birth Defects Res A Clin Mol Teratol. 2013 Feb;97(2):95-100. doi: 10.1002/bdra.23114.
Underlying mechanisms are unknown by which folic acid use in early pregnancy may reduce risks of orofacial clefts. Thymidylate synthase (TYMS) is a folate-dependent enzyme that catalyzes reductive methylation of deoxyuridylate to thymidylate, thereby playing a central role in DNA synthesis and repair. We investigated two TYMS functional variants (a 28-bp tandem repeat in the promoter enhancer region of the 5'-UTR; and TYMS 1494del6 (rs16430): a 6-bp deletion in the 3'-UTR) for their risk of cleft palate (CP) and of cleft lip with/without CP (CLP). We investigated effect measure modification between these variants and maternal folate intake for cleft risk.
This case-control study included deliveries from July 1999 to June 2003 from select areas of California. Case groups included CLP or CP alone. Nonmalformed, liveborn controls were randomly selected. Maternal interviews provided information on vitamin use and dietary folate intake. DNA was derived from newborn bloodspots.
Data were available for 304 CLP cases, 123 CP cases, and 581 controls. 1496del6 variants did not appear to influence risk of CP or CLP. Homozygosity for the 28-bp VNTR variant influenced CP risk (odds ratios, OR = 1.8, 95% confidence interval, 1.1-3.1), particularly among Hispanic infants, OR 2.1 (1.0-4.6). Effect measure modification was observed between the 28-bp VNTR and combined folate intake for CP with an OR of 10.0 (1.6-60.9).
Although these findings are consistent with biological mechanisms, they were based on relatively small sample sizes and may represent false-positive discoveries. Replication is warranted in other populations.
妊娠早期使用叶酸可降低口面部裂隙风险的潜在机制尚不清楚。胸苷酸合成酶（TYMS）是一种叶酸依赖性酶，催化脱氧尿苷酸还原甲基化生成胸苷酸，从而在DNA合成和修复中起核心作用。我们研究了两种TYMS功能变体（5'-UTR启动子增强子区域的28-bp串联重复序列；以及TYMS 1494del6（rs16430）：3'-UTR中的6-bp缺失）与腭裂（CP）和唇裂伴/不伴CP（CLP）的风险。我们研究了这些变体与孕妇叶酸摄入量之间对裂隙风险的效应测量修正。
这项病例对照研究纳入了1999年7月至2003年6月加利福尼亚特定地区的分娩病例。病例组包括单独的CLP或CP。随机选择无畸形的活产对照。通过产妇访谈获取维生素使用和膳食叶酸摄入量的信息。DNA来自新生儿血斑。
有304例CLP病例、123例CP病例和581例对照的数据。1496del6变体似乎不影响CP或CLP的风险。28-bp VNTR变体的纯合性影响CP风险（优势比，OR = 1.8，95%置信区间，1.1 - 3.1），尤其是在西班牙裔婴儿中，OR为2.1（1.0 - 4.6）。观察到28-bp VNTR与CP的联合叶酸摄入量之间存在效应测量修正，OR为10.0（1.6 - 60.9）。
尽管这些发现与生物学机制一致，但它们基于相对较小的样本量，可能代表假阳性发现。有必要在其他人群中进行重复研究。
