卫生研究

目的研究5,10-亚甲基四氢叶酸还原酶(MTHFR)C677T和A1298C位点,蛋氨酸合成酶(MS)A2756G位点,以及蛋氨酸合成酶还原酶(MTRR)A66G位点的单核苷酸多态性(SNPs)和先天性心脏病(CHD)的关联。方法采用病例-对照研究,限制相应条件于2016年1月—2017年4月在河北省儿童医院心脏外科收集了200名CHD患儿作为病例组,200名正常体检儿童作为对照组。通过聚合酶链式反应(PCR)后Sanger测序的分析方法检测两组儿童的MTHFR C677T和A1298C位点、MS A2756G位点以及MTRR A66G位点的基因型及其分布,分析上述4个SNP位点与整体CHD和单一以及多发畸形型CHD发病风险之间的关系。结果 MTHFR C677T位点等位基因T携带者相对于等位基因C携带者发生CHD的OR=2.47(95%CI 1.86³.29,P<0.001)。与纯合子CC型比较,杂合子CT个体患CHD的OR=2.32(95%CI 1.35³.98,P<0.05),而突变型纯合子TT个体患CHD的风险是CC个体的5.37倍(95%CI 3.01⁹.60,P<0.001);MTHFR A1298C位点等位基因C携带者相比于等位基因A携带者发生CHD的OR=0.53(95%CI 0.36⁰.77,P<0.05)。杂合子AC个体患病风险低于野生型纯合子AA个体(OR=0.41,95%CI 0.26⁰.64,P<0.001);在分类后的单一及多发畸形型CHD中,以上两个位点的等位基因频率及基因型频率依然具有统计学意义(P<0.05)。以上两位点的组合基因型分析显示:相比于携带双野生型CC/AA的个体,携带CT/AA个体的患病风险增加到了4.65倍(95%CI 2.16~10.02),TT/AA型个体增加到了7.05倍(95%CI 3.37~14.79)。统计结果表明MS A2756G和MTRR A66G位点对整体CHD以及对分类后的单一及多发畸形型CHD的发生均无影响(P>0.05)。结论 MTHFR C677T位点的突变型等位基因T可能为CHD的危险因素,A1298C位点的突变型等位基因C可能是CHD的保护因素,这两个位点对CHD的发生可能存在联合作用。

Objective To investigate the association between single nucleotide polymorphisms( SNPs) of 5,10-methylenetetrahydrofolate reductase( MTHFR) C677T,A1298C,methionine synthase( MS) A2756G,methionine synthase reductase( MTRR) A66G and the risk of congenital heart disease( CHD).Methods By restricting the corresponding conditions, a case-control study was performed.We collected 200 congenital heart disease children as case group and 200 normal children as control group admitted to the Department of cardiac surgery,Children 's Hospital of Hebei Province from January 2016 to April 2017.The genotype of MTHFR C677T, A1298C, MS A2756G,and MTRR A66G polymorphisms were detected by Sanger sequencing followed PCR.Assessing the relationships between 4 SNPs and the risk of whole CHD and different types of CHD.Results The mutant allete T of MTHFR C677T had contribute to the risk of developing CHD( OR = 2.47,95% CI 1.86-3.29,P < 0.001).Compared with the wild CC genotype,heterozygosity CT had a higher risk of CHD( OR = 2.32,95% CI 1.35-3.98,P < 0.05),the homozygous mutant genotype TT increased the risk of CHD by 5.37( 95% CI 3.01-9.60,P < 0.001).The mutant allele C of MTHFR A1298C was a protective factor for CHD( OR = 0.53,95% CI 0.36-0.77,P < 0.05).Compared with the wild AA genotype,heterozygosity AC had a lower risk of CHD( OR = 0.41,95% CI0.26-0.64,P < 0.001).After typing,the allele frequencies and genotypes frequencies of the above two SNPs were still statistically significant( P < 0.05).The combined genotype analysis of the above two SNPs showed that: compared with the CC/AA genotype,individuals with CT/AA had a higher risk of CHD( OR = 4.65,95% CI 2.16-10.02),the TT/AA type increased to 7.05( 95% CI 3.37-14.79).However,the polymorphisms of MS A2756G and MTRR A66G had no significant relationship with the risk of CHD( P > 0.05).Conclusion The mutant allele T of MTHFR C677T may be a risk factor for CHD and the mutant allele C of A1298C may be a protective factor for CHD.These two SNPs may have a joint effect on the occurrence of CHD.