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APOE Genotype-Function Relationship: Evidence of −491 A/T Promoter Polymorphism Modifying Transcription Control but Not Type 2 Diabetes Risk

Geng, Hua; Law, Peggy P. Y.; Ng, Maggie C. Y.; Li, Ting; Liang, Li-Yun; Ge, Tiang-Fang; Wong, Kam-Bo; Liang, Chun; Ma, Ronald C.; So, Wing-Yee; Chan, Juliana C. N.; Ho, Yuan-Yuan

Background: 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. Methodology/Principal Findings: 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. Conclusions/Significance: 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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Biostatistics
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August 18, 2013