APOE genotype-function relationship: evidence of -491 A/T promoter polymorphism modifying transcription control but not type 2 diabetes risk.
APOE genotype-function relationship: evidence of -491 A/T promoter polymorphism modifying transcription control but not type 2 diabetes risk.
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DOI：
10.1371/journal.pone.0024669
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ho YY
中科院分区：
文献类型：
--
作者：
Geng H;Law PP;Ng MC;Li T;Liang LY;Ge TF;Wong KB;Liang C;Ma RC;So WY;Chan JC;Ho YY
载脂蛋白E基因（APOE）编码多态性改变阿尔茨海默病、2型糖尿病和冠心病的风险。除了编码变体，APOE启动子的单核苷酸多态性（SNP）也被证明可以改变阿尔茨海默病的风险。本研究从分子水平和生理水平探讨了APOE基因启动子多态性的基因型与功能的关系，基因转录控制和2型糖尿病的风险。在分子研究中，APOE − 491 A/T（rs 449647）多态性对基因转录的影响通过双荧光素酶报告基因测定来评估。-491 A到T的替换降低了克隆的APOE启动子的活性（p<0.05）（-1017到+406）。以APOE启动子的−501 ~ −481核苷酸序列为诱饵，通过酵母单杂交系统筛选人脑cDNA文库，得到了作为相互作用因子之一的内质网应激反应基因ATF 4。电泳迁移率变动分析（EMSA）和染色质免疫沉淀（ChIP）分析进一步证实了ATF 4和APOE启动子之间的物理相互作用。ATF 4的过表达刺激APOE表达，而针对ATF 4的siRNA抑制该基因的表达。然而，APOE启动子和ATF 4之间的相互作用不是− 491 A/T特异性的。在生理水平上，研究APOE基因启动子多态性与2型糖尿病的基因型-功能关系。在630例病例和595例对照中，对三种APOE启动子SNP-491 A/T、-219 G/T（rs 405509）和+113 G/C（rs 440446）进行基因分型，并检测其与香港中国人2型糖尿病的相关性。未检测到SNP或单倍型与2型糖尿病相关。在分子水平上，多态性-491 A/T和ATF 4引起APOE基因表达的独立控制。在生理水平上，未检测到所研究的APOE启动子SNPs与香港中国人2型糖尿病之间的基因型风险关联。
The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE −491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The −491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (−1017 to +406). Using the −501 to −481 nucleotide sequence of the APOE promoter as a ‘bait’ to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not −491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs −491A/T, −219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. At molecular level, polymorphism −491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese.
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影响因子：
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