华中地区神经管缺陷家庭叶酸代谢相关基因的单核苷酸多态性研究

Single nucleotide polymorphisms of folate metabolism pathway genes in central chinese families with neural tube defects

目的通过对叶酸代谢相关基因的单核苷酸多态性（single nucleotide polymorphism，SNP）与环境危险因子交互作用的关联分析，寻找神经管缺陷（neural tube defects，NTD）致病基因及环境危险因素。方法收集NTD流产胎儿组织标本或患儿血标本（n＝278）及其正常双亲的血标本（n＝478），记录母亲围孕期补充叶酸、糖尿病、服药史等情况。采用CEQ8800系统进行多重SNP分析，对所有样本叶酸代谢相关的12个基因共28个SNP测序。通过病例-双亲对照研究及传递／不平衡检验，分析SNP与环境危险因子（孕期补充叶酸、母亲糖尿病、孕期服药史）的交互作用对NTD发病的影响。结果亚甲基四氢叶酸还原酶（基因为MTHFR）rsl801133与NTD的关联具有统计学意义，而且环境风险因子（未补充叶酸、母亲糖尿病）对NTD的发生起增效作用；而甜菜碱同型半胱氨酸甲基转移酶（基因为BHMT）rs3733890仅在未补充叶酸层与NTD存在连锁不平衡，基因型本身并不能单独导致疾病；而其他基因的SNP与NTD的发生没有显著关联。结论MTHFRrsl801133是NTD的危险因子，而BHMTrs3733890不是NTD的独立危险因子。未来尚需要对更大的样本进行基因与基因、基因与环境交互作用的研究以探讨NTD的发病原因。

Objective To investigate the contribution of single nucleotide polymorphisms （SNP） variation in folate metabolism pathway genes and its interaction with environmental risk factors to the etiology of NTD. Methods In 275 families from central China, a total of 278 aborted fetal tissues or blood samples were collected from NTD individuals, 478 maternal and/or paternal blood samples were also obtained as controls. Folate supplementation, maternal diabetes mellitus and medication before pregnancy and during the first trimester of pregnancy were investigated. SNP analyses of all samples were performed by CEQ 8800. Case-parent control study and transmission/disequilibrium tests （TDT） were performed according to environmental cofactors stratification to evaluated 28 SNP in 12 folate pathway genes associated with human NTD. Results Only gene MTHFR rs1801133 was significantly associated with NTD, and synergistic effects of environmental risk factors （no folate supplementation and maternal diabetes） were shown on the occurrence of NTD. Linkage disequilibrium between BHMT rs3733890 and NTD existed in case of no folate supplementation, whereas the genotype alone did not contribute to the etiology of NTD. Other SNP were not significantly associated with NTD. Conclusions MTHFR rs1801133 is a risk factor of NTD, but BHMT rs3733890 is not an independent risk factor. Further investigations in folate and methionine cycle genes are requird in larger scale to enclose the interactions between gene and gene, or gene and environmental factors.