HIF-1α基因启动子-1946位点r基因多态性与紫绀型先天性心脏病低氧耐受的相关性

摘要

Objective To identify potential association of gene polymorphism of hypoxia inducible factor -1α( HIF-1α) associated with hypoxic tolerance in cyanotic congenital heart disease ( CCHD) .Methods HIF-1αwas selected sequenced in 97 CCHD cases and 108 acyanotic congenital heart disease ( ACHD ) cases .Different distribution of polymorphic site was detected after bioinformatics analysis .The related variants were confirmed using Sanger sequen-cing .For the polymorphic site in promoter region of HIF-1α, different genotype of human HIF-1αpromoter-luciferase reporter gene vectors were respectively constructed , and the vectors were transiently transfected into HEK 293T and H9C2 cells.Dual-luciferase assay was performed to reflect the transcriptional activity of different genotype HIF-1αpromoter .Results The mutation rate of HIF-1α-1496 in CCHD population was significantly higher than that in ACHD population(P<0.05).Transcriptional activity of DD genotype was higher than that of AA genotype (P<0.05).Conclusions HIF-1α-1946 is associated with hypoxia tolerance of CCHD .Transcription activity of DD genotype was increased significantly , which may be one of the genetic mechanisms of hypoxia tolerance .%目的 研究低氧诱导因子-1α(HIF-1α)基因多态性与紫绀型先天性心脏病(CCHD)低氧耐受能力是否具有相关性.方法 用靶向捕获技术,对97例CCHD患儿和108例非紫绀型先天性心脏病(ACHD)患儿HIF-1α基因二代测序;生物信息学分析后找出差异分布的多态位点;用Sanger测序验证.针对HIF-1α启动子区多态位点,构建不同基因型HIF-1α启动子-荧光素酶报告基因载体;转染HEK293T和H9C2细胞;用双荧光素酶报告基因检测系统,分析HIF-1α不同基因型启动子活性.结果 CCHD组HIF-1α启动子区-1946位点A碱基删除变异频率高于ACHD组(P<0.05).与AA基因型比较,DD基因型HIF-1α启动子转录活性更高(P<0.05).结论 HIF-1α基因-1946位点与CCHD耐受低氧能力相关,DD基因型HIF-1α转录活性明显增高,可能是耐受低氧的分子遗传学机制之一.