Gene-gene interaction between the cystathionine β-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C>T polymorphism on homocysteine levels and risk for neural tube defects
Gene-gene interaction between the cystathionine β-synthase 31 base pair variable number of tandem repeats and the methylenetetrahydrofolate reductase 677C>T polymorphism on homocysteine levels and risk for neural tube defects
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DOI：
10.1016/s1096-7192(03)00021-0
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发表时间：
2003-03-01
影响因子：
3.8
通讯作者：
Blom, HJ
中科院分区：
文献类型：
--
作者：
Afman, LA;Lievers, KJA;Blom, HJ
简介：大多数研究表明，NTD 儿童的母亲同型半胱氨酸水平升高，表明同型半胱氨酸代谢紊乱是 NTD 的危险因素。叶酸通过将同型半胱氨酸重新甲基化为蛋氨酸来降低同型半胱氨酸水平。同型半胱氨酸可通过维生素 B6 依赖性酶 CBS 不可逆地转化为胱硫醚。最近，我们的研究小组发现，CBS 基因中的 31 bp VNTR 与 CVD 人群中蛋氨酸负荷后 CBS 活性降低和 tHcy 水平升高相关。目的：我们研究的目的是调查该 VNTR 是否影响 tHcy 水平和 NTD 风险。此外，我们还评估了维生素 B6 作为效果调节剂在这种可能的相互作用中的作用。我们检查了 MTHFR 677C > T 多态性可能存在的基因间相互作用。我们针对这种 CBS 31 bp VNTR 筛选了 88 名 NBD 患者、100 名母亲、88 名父亲和 505 名对照的基因组 DNA。 结果：在本研究群体中，观察到 5 个不同的等位基因，其 31 bp 重复次数为 16、17、18、19 和 21 倍，构成 10 种不同的基因型。与 17/18 和 18/19 VNTR 基因型相比，最常见的 18/18 VNTR 基因型与较高的 tHcy 水平相关。维生素 B6 水平不影响这种关联。此外，未发现与 NTD 风险相关。 CBS VNTR 与 MTHFR 677C > T 多态性的组合显示，与 MTHFR 677C > T 多态性纯合突变体受试者中的 17-18 个同龄人相比，18-18 个个体的同型半胱氨酸水平额外增加。 结论：本研究表明，CBS 基因中 31 bp 重复元件的数量影响 tHcy 水平。这种 VNTR 似乎与 NTD 风险增加无关。 (C) 2003 年爱思唯尔科学（美国）。版权所有。
Introduction: Most studies showed that mothers of children with NTD have elevated homocysteine levels pointing to a disturbed homocysteine metabolism as a risk factor for NTD. Folate lowers homocysteine levels by remethylation of homocysteine to methionine. Homocysteine can be irreversibly converted to cystathionine by the vitamin B6-dependent enzyme CBS. Recently, our group showed that a 31 bp VNTR in the CBS gene was associated with decreased CBS activity and increased tHcy levels after methionine loading in a CVD population.Aim: The aim of our study was to investigate whether this VNTR influences tHcy levels and risk for NTD. In addition, we assessed the role of vitamin B6 as an effect modifier in this possible interaction. We examined possible gene-gene interaction with the MTHFR 677C > T polymorphism. We screened genomic DNA of 88 NBD patients, 100 mothers, 88 fathers, and 505 controls for this CBS 31 bp VNTR.Results: In this study population five different alleles with 16,17, 18, 19, and 21 times the 31 bp repeat were observed that constituted 10 different genotypes. The most common 18/18 VNTR genotype was associated with higher tHcy levels compared with the 17/18 and 18/19 VNTR genotypes. Vitamin B6 levels did not influence this association. In addition, no association with risk for NTD was found. Combination of the CBS VNTR with the MTHFR 677C > T polymorphism revealed an additional increase in homocysteine levels in 18-18 individuals compared with 17-18 peers within subjects homozygous mutant for the MTHFR 677C > T polymorphism.Conclusions: The present study indicates that the number of 31 bp repeat elements in the CBS gene influences tHcy levels. This VNTR seems not to be associated with an increased risk for NTD. (C) 2003 Elsevier Science (USA). All rights reserved.