SHMT1基因启动子的rs638416位点与先天性心脏病的相关性

Association of rs638416 in SHMT1 promoter and congenital heart diseases

目的 通过研究丝氨酸羟甲基转移酶（serine hydroxy methyl transferase,SHMT1）基因启动子区的单核苷酸多态性（single nucleotide polymorphism,SNP）来探讨该基因与先天性心脏病 （congenital heart disease,CHD）的相关性。方法 选取来自山东省的201例CHD患儿（病例组）和192例正常儿童（对照组）,采用Sanger测序法对rs638416和rs117940726两个位点的基因分型进行病例-对照研究,进一步用双荧光素酶报告基因分析其是否为功能性SNP。结果 两个SNP位点的基因型分布在病例组和对照组中均符合Hardy-Weinberg平衡;单位点分析显示rs638416位点G等位基因在病例组中分布频率显著高于对照组 （P=0.009）。经非条件Logistic回归分析确定,Log-additive模型最适用于分析rs638416,且该模型下统计学差异最显著 （OR=1.49,95%CI：1.11- 2.01,P=0.007 4）;双荧光素酶报告基因分析显示带有G等位基因的启动子序列转录效率较带有C等位基因的启动子序列低36% （P=0.013）。结论 rs638416位点能影响SHMT1转录效率,并与心脏发育异常相关,提示rs638416位点G等位基因是山东人群CHD发生的遗传风险因子。

Objective To explore the association between single nucleotide polymorphism （SNPs） in the promoter region of cytoplasmic serine hydroxy methyl transferase （SHMT1） and congenital heart disease （CHD）. Methods We performed a case-control study including 201 CHD patients and 192 control participants from Shandong province,China through Sanger sequencing of rs638416 and rs117940726.Then we conducted luciferase reporter gene assays to confirm if they were functional SNP. Results These two SNPs were genotyped and they were in Hardy-Weinberg equilibrium both in control and case groups.The single locus analysis revealed the genotype distribution of rs638416 was significant different between case patients and control subjects （P=0.009）.In the unconditional Logistic regression analysis,Log-additive model was the most suitable model to analysis rs638416,and in this model association data showed the most significant statistical different （OR=1.49,95%CI：1.11-2.01,P=0.007 4）.The result of luciferase reporter gene assays also showed 36% transcription activity reduction （P=0.0013） of the promoter region containing G allele when compared to the promoter region containing G allele. Conclusions We confirmed rs638416 reduced the transcription activity of SHMT1 and may involve with abnormal heart development.The G allele of rs638416 is a genetic risk factor of CHD in Shandong population.