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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.

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