Associations between polymorphisms within the thymidylate synthase gene and spina bifida
Associations between polymorphisms within the thymidylate synthase gene and spina bifida
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DOI：
10.1002/bdra.10029
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发表时间：
2003-11-01
影响因子：
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通讯作者：
Finnell, RH
中科院分区：
文献类型：
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作者：
Volcik, KA;Shaw, GM;Finnell, RH
背景：影响酶活性的胸苷酸合成酶(TS)基因内的多态可能会影响血浆叶酸水平，并间接影响血浆同型半胱氨酸浓度。我们调查了TS多态是否与脊柱裂(SB)风险有关，因为SB风险的降低与叶酸代谢有关。方法：从新生儿筛查血斑中提取基因组DNA，这些血点来自SB患儿和随机选择的正常对照婴儿。采用聚合酶链式反应(PCR)和限制性片段长度多态性(RFLP)方法检测TS基因启动子增强子区(TSER)28个碱基串联重复序列和3‘UTR6个碱基缺失两种多态的基因频率。此外，对TS基因的所有七个外显子进行了测序，以确定该基因编码区内的变异。结果：我们发现TSER2/2纯合子基因与SB婴儿的风险略有增加相关(优势比[OR]=1.4[0.8-2.4]，p=0.1)。当队列被分成不同的种族组时，在非西班牙裔白人病例中，这种风险是TSER 2/2纯合子基因的4倍(OR=4.01.8-8.8，p=0.001)，是3‘Utr+/+纯合子基因的3倍(OR=3.61.3-10.1，p=0.02)。TSER，3‘UTR(2/2，+/+)基因组合显示，在该特定种族中，SB的风险增加了4倍以上(OR=4.7[1.1-19.8]，p=0.04)。结论：这项研究首次评估了TS基因多态与SB发病风险的关系。目前的研究结果表明，TS基因非翻译区的多态与非西班牙裔白人患SB的风险增加4倍或更多有关，但在西班牙裔白人、非裔美国人或亚裔美国人中不相关。(C)2003年Wiley-Liss，Inc.
BACKGROUND: Polymorphisms within the thymidylate synthase (TS) gene that influence enzyme activity may affect plasma folate levels and, indirectly, plasma homocysteine concentrations. We investigated whether TS polymorphisms contribute to spina bifida (SB) risk, given that a reduction in the risk of SB has been linked to folate metabolism. METHODS: Genomic DNA was extracted from newborn-screening blood spots obtained from case infants with SB, and randomly selected, nonmalformed control infants. Genotype frequencies of two polymorphisms in the TS gene-a 28-bp tandem repeat in the promoter enhancer region (TSER) and a 6-bp deletion in the 3'UTR-were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Additionally, all seven exons of the TS gene were sequenced to identify variations within the coding region of the gene. RESULTS: We found that the TSER 2/2 homozygous genotype was associated with a slightly increased risk for SB infants (odds ratio [OR] = 1.4 [0.8-2.4], p = 0.1). When the cohort was divided into separate ethnic groups, this risk increased by 4-fold with the TSER 2/2 homozygous genotype (OR = 4.0 [1.8-8.8], p = 0.001), and by 3-fold with the 3'UTR +/+ homozygous genotype (OR = 3.6 [1.3-10.1], p = 0.02) in non-Hispanic white cases. The combined TSER,3'UTR (2/2, +/+) genotype showed a more than 4-fold increased risk for SB within this specific ethnic group (OR = 4.7 [1.1-19.8], p = 0.04). CONCLUSIONS: This study is the first to evaluate how TS polymorphisms contribute to the risk of SB. The current findings indicate that polymorphisms in the untranslated regions of the TS gene are associated with 4-fold or more increased risks of SB in non-Hispanic whites, but not in Hispanic whites, African-Americans, or Asian-Americans. (C) 2003 Wiley-Liss, Inc.