Johnson William G, Stenroos Edward S, Spychala John R, Chatkupt Sansnee, Ming Sue X, Buyske Steven
Division of Neurogenetics, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 671 Hoes Lane, Piscataway, NJ 08854, USA.
Am J Med Genet A. 2004 Feb 1;124A(4):339-45. doi: 10.1002/ajmg.a.20505.
Up to 72% of spina bifida cystica (SB) is preventable by maternal periconceptual folic acid supplementation. The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene and some other functional polymorphisms are risk factors for SB in some populations. However, despite extensive study, the genetic risk factors for SB are incompletely understood. Polymorphic alleles that diminish bioavailability of reduced folate in the mother during pregnancy could contribute to SB in her fetus, acting in the mother as teratogenic alleles. We recently discovered a polymorphic 19 bp deletion allele (frequency 0.45) within intron-1 of dihydrofolate reductase (DHFR) that is a good candidate for such a genetic factor. Since there is precedence for intron-1 regulatory elements and the deletion allele removes a potential Sp1 transcription factor binding site, we hypothesized that the deletion allele could be functional and act in SB mothers to increase the risk of SB in her fetus. We found that homozygosity for this deletion allele was significantly more frequent in SB mothers, but not in SB fathers or patients, compared with controls and was associated with a significantly increased odds ratio (OR) (2.035) of being an SB mother compared with other genotypes. Genotype distribution obeyed the constraints of Hardy-Weinberg equilibrium in controls, SB patients and fathers, but not in SB mothers. If confirmed, these findings could lead to improved forms of folate supplementation for pregnancy. About half of dietary folates and all of folic acid supplements must be reduced by DHFR to be available for mother and fetus. Reduced folates could be preferable for supplements during pregnancy to prevent SB.
通过孕期前补充叶酸，高达72%的脊柱裂囊肿型（SB）是可预防的。亚甲基四氢叶酸还原酶（MTHFR）基因的C677T等位基因及其他一些功能多态性在某些人群中是SB的危险因素。然而，尽管进行了广泛研究，SB的遗传危险因素仍未完全明了。孕期母体内降低型叶酸生物利用度的多态性等位基因可能导致其胎儿发生SB，在母亲体内起致畸等位基因的作用。我们最近在二氢叶酸还原酶（DHFR）基因的内含子1中发现了一个19 bp缺失的多态性等位基因（频率为0.45），它很可能是这样一种遗传因素。由于内含子1调控元件存在先例，且缺失等位基因去除了一个潜在的Sp1转录因子结合位点，我们推测该缺失等位基因可能具有功能，并在SB母亲体内增加其胎儿患SB的风险。我们发现，与对照组相比，该缺失等位基因的纯合子在SB母亲中显著更常见，但在SB父亲或患者中并非如此，并且与作为SB母亲的显著增加的优势比（OR）（2.035）相关，与其他基因型相比。对照组、SB患者和父亲的基因型分布符合哈迪-温伯格平衡的限制，但SB母亲不符合。如果得到证实，这些发现可能会带来改善孕期叶酸补充形式的方法。膳食叶酸的大约一半和所有叶酸补充剂都必须由DHFR还原才能供母亲和胎儿使用。孕期补充还原型叶酸可能更有利于预防SB。
