叶酸代谢关键酶基因多态性与儿童神经管缺陷的相关性

Association between single nucleotide polymorphisms of folate metabolism pathway genes and neural tube de- fects in children

目的研究叶酸代谢通路中关键酶单核苷酸多态性（SNPs）与中国北方汉族儿童神经管缺陷（NTDs）的相关性。方法以中国北方汉族152例NTDs患儿和169例对照者为研究对象进行病例一对照研究。采用SequenomMassARRAYSNP分型技术对5个基因的16个SNPs位点进行基因分型。应用SIFT和PolyPhen程序预测评价点突变对蛋白质功能的影响。结果亚甲基四氢叶酸脱氢酶1（MTHFDl）基因rs2236225位点等位基因和基因型频率在病例组和对照组中的分布差异具有统计学意义（X2=5．292、6．080；P=0．021、0．048），且A等位基因和AA基因型携带儿童发生NTDs的风险高于G等位基因和GG基因型携带者（OR=1．500，95％CI1．061～2．120；OR=2．862，95％CI1．022～8．015）。亚甲基四氢叶酸还原酶（MTHFR）基因rsl801133位点等位基因和基因型频率在病例组和对照组中的分布差异具有统计学意义（X2=7．403、6．973；P=0．007、0．031），且T等位基因和，IT基因型携带儿童发生NTDs的风险高于C等位基因和cc基因型携带者（OR=1．552，95％C11．130～2．131；OR=2．344，95％C11．233—4．457）；甲硫氨酸合成酶还原酶（MTRR）基因rsl801394位点等位基因和基因型频率在病例组和对照组中的分布差异具有统计学意义（z2=6．365、6．219；P=0．012、0．045），且G等位基因和GG基因型携带儿童发生NTDs的风险高于A等位基因和AA基因型携带者（OR=1．553，95％CI1．102～2．188；OR=2．355，95％CI1．044～5．312）。MTHFR基因rsl801133和MTRR基因rsl801394的SIFT预测结果为damaging，PolyPhen预测结果为probablydamaging，均提示为有害突变。结论MTHFDI基因rs2236225、MTHFR基因rsl801133及MTRR基因rsl801394位点多态性与中国北方汉族儿童NTDs发生具有相关性，证实叶酸代谢通路中关键酶基因的变异是NTDs遗传易感性因素之一。

Objective To analyze the association between single nucleotide polymorphisms （SNPs） of folate metabolism pathway genes and neural tube defects （NTDs） in children of Han population in northern China. Methods One hundred and fifty - two NTDs patients and 169 controls in a case - control study were examined. Sixteen SNPs in 5 genes were genotyped by Sequenom MassARRAY. Prediction of effects of mutations on protein function was performed with SIFT and PolyPhen programs. Results The distribution of allele and genotype frequencies of methylenetetrahydro- folate dehydrogenase 1 （ MTHFD1 ） rs2236225 loci was significantly different between NTDs group and the healthy con- trol group （x2 = 5. 292,6. 080 ; P = 0.021,0. 048 ）, and the children with A allele and AA genotype were associated with increased NTDs risk compared with G allele and GG genotype （OR = 1. 500,95% CI 1. 061 -2. 120; OR = 2. 862, 95% CI 1. 022 - 8. 015 ）. The distribution of allele and genotype frequencies of methylenetetrahydrofolate reductase （MTHFR） rs1801133 loci was significantly different between NTDs group and the healthy control group（x2 = 7. 403, 6. 973 ;P =0. 007,0.031 ）,and the children with T allele and TT genotype were associated with increased NTDs risk compared with C allele and CC genotype（ OR = 1. 552,95% CI 1. 130 - 2. 131 ; OR = 2. 344,95% CI 1. 233 - 4. 457 ）. The distribution of allele and genotype frequencies of methionine synthase reductase （MTRR） rs1801394 loci was sig- nificantly different between NTDs group and the healthy control group（x2 = 6. 365,6. 219 ;P =0. 012,0. 045 ）, and the children with G allele and GG genotype were associated with increased NTDs risk compared with A allele and AA geno- type（ OR = 1. 553,95% CI 1. 102 -2. 188 ;OR =2. 355,95% CI 1. 044 -5. 312）. There was no difference in other loci among different genotypes or alleles. SIFT and Polyphen programs showed that the prediction results were damaging and probably damaging （MTHFR rs1801133 and MTRR rs1801394）. Conclusions The rs2236225 of MTHFD1 gene, rs1801133 of MTHFR gene and rs1801394 of MTRR gene are associated with NTDs in children of Han population in Northern China. The further results confirmed that the genetic variation of folate metabolism pathway genes is one of NTDs susceptibility factors.