Boyles Abee L, Billups Ashley V, Deak Kristen L, Siegel Deborah G, Mehltretter Lorraine, Slifer Susan H, Bassuk Alexander G, Kessler John A, Reed Michael C, Nijhout H Frederik, George Timothy M, Enterline David S, Gilbert John R, Speer Marcy C
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Environ Health Perspect. 2006 Oct;114(10):1547-52. doi: 10.1289/ehp.9166.
Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results.
Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation.
In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase.
Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission.
BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene-gene interactions in large data sets.
叶酸代谢途径基因已被研究与神经管缺陷（NTDs）的关联，因为补充叶酸可降低这种使人衰弱的出生缺陷的风险。大多数研究分别针对这些基因进行，不同人群的研究结果往往相互矛盾。
我们的研究评估了几个叶酸途径基因与人类NTDs的关联，并纳入了一个环境辅助因素：孕妇叶酸补充情况。
在304个患有脊髓脊膜膨出或无脑畸形的美籍高加索NTD家庭中，我们检测了11个基因中的28个多态性位点：叶酸受体1、叶酸受体2、溶质载体家族19成员1、转钴胺素II、亚甲基四氢叶酸脱氢酶1、丝氨酸羟甲基转移酶1、5,10-亚甲基四氢叶酸还原酶（MTHFR）、5-甲基四氢叶酸-同型半胱氨酸甲基转移酶、5-甲基四氢叶酸-同型半胱氨酸甲基转移酶还原酶、甜菜碱-同型半胱氨酸甲基转移酶（BHMT）和胱硫醚-β-合酶。
在整个数据集中，只有BHMT中的单核苷酸多态性（SNP）有显著关联；当母亲在受孕前服用含叶酸的营养补充剂时，这种显著性最强。当数据按MTHFR rs1801133不耐热T等位基因从父母向后代的优先传递进行分层时，BHMT SNP rs3733890的显著性更强。当按母亲补充情况、MTHFR或BHMT等位基因传递进行分层时，叶酸途径基因中的其他SNP在一些分析中具有边缘显著性。
在我们的数据集中BHMT rs3733890有显著关联，而MTHFR rs1801133不是主要风险因素。对叶酸和甲硫氨酸循环基因的进一步研究将需要广泛的SNP基因分型和/或重测序以识别新的变异体，纳入环境因素，并在大数据集中研究基因-基因相互作用。
