叶酸代谢相关基因的多态性与唐氏综合征的关系

Relationship between genetic polymorphisms of folate metabolism, plasma homocysteine levels and risk of Down syndrome

目的研究叶酸代谢中亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase，MTHFR）基因的的遗传多态性是否与唐氏综合征（downsyndrome，DS）的发生相关。方法选择100例生育过DS患儿的汉族母亲为研究组和100例相匹配的汉族母亲为对照组，使用PCR-RFLP和MGB-Taqman实时PCR方法检测MTHFR677和MTHFR1298的基因型，化学发光法检测血浆同型半胱氨酸（homoeysteine，HCY）的水平。结果MTHFR677和MTHFR 1298一个和／或两个等位基因的变异可使生育DS患儿的风险率分别增加2．37倍（95％CI：1．32～4．27）和1．97倍（95％CI：1．04～3．75）。同时合并MTHFR677CT和1298AC／CC可使DS的发病风险率显著增高，OR=5．62（95％CI：1．86～17．03），而MTHFR677TT合并1298AC／CC的基因型组合使OR=11．84（95％CI：1．39-100．62）。研究组血浆HCY水平显著高于对照组[（9．04±3．85）μmol／L和（6．53±2．06）μmol／L，P〈0．01]。MTHFR677一个和／或两个等位基因C→T的变异，使研究组和对照组HCY水平均显著增加（P〈0．05）。单纯存在MTHFR1298A／C时两组血浆HCY水平无统计学差异（P〉0．05）。同时存在MTHFR677CT／TT和1298AC／CC基因组合可使血浆HCY水平增高（P〈0．05）。结论HCY／叶酸代谢相关基因的多态与汉族妇女生育DS患儿的风险相关，且可能存在基因的协同作用。

Objective To investigate whether genetie polyrnorphisms of methylenetetrahydrofolate reductase （MTHFR） contribute to the risk of Down syndrome（DS）. Methods Altogether, 100 Chinese mothers who had given birth to DS babies （study group） and 100 matched mothers （control） were chosen and all were Han nationality. Genotypes of MTHFR 677 and MTHFR 1298 were determined by PCR-RFLP and MGB-Taqman real-time PCR. The concentration of plasma homoeysteine （HCY） was measured by chemiluminesenee. Results The mutations of one or both alleles of MTHFR 677 and MTHFR 1298 were associated with a 2.37-fold（95%CI： 1.19-3.05） and 1.97-fold（95%CI： 1.04-3. 75） increase in the risk of having a child with DS. Combination of MTHFR 677CT and 1298AC/CC genotype had a 5.62-fold increased risk of having a child with DS（95%CI： 1.86-17. 03） and the combination of MTHFR 677TT and MTHFR 1298AC/CC genotype was significantly associated with an increased risk of DS（OR： 11.84, 95% CI： 1.39-100. 62）. The mean plasma HCY concentration was significantly higher in the study group than that of control [（9.04±3.85） μmol/L vs （6.53±2.06） μmol/L, P〈0.01）]. The presence of 677C→T substitution in one or both alleles was associated with increased plasma HCY in both groups （P〈 0. 05）. However, MTHFR 1298A/C mutation alone did not significantly change the level of HCY in neither groups （P〉0. 05）. Higher HCY level was found in the genotype-pairs of MTHFR 677CT/TT and 1298AC/CC （P〈0. 05）. Conclusions Maternal genetic polymorphisms of homocysteine/folate pathway is the risk factor for DS fetus in Han nationality women in China, and a genetic synergistic effect could not be excluded.