The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes

Background: We investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) to determine whether a highly polymorphic, intronic poly-T within this region (rs10524523; hereafter, 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified as S, short; L, long; and VL, very long based on the number of T residues. Methods: We evaluated differences in APOE messenger RNA (mRNA) and TOMM40 mRNA levels as a function of the 523 genotype in two brain regions from APOE epsilon 3/epsilon 3 white autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system. Results: The expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40 mRNA levels were higher in VL homozygotes compared with S homozygotes in the temporal and occipital cortexes from normal and LOAD cases. Results of a luciferase reporter system were consistent with the human brain mRNA analysis; the 523 VL poly-T resulted in significantly higher expression than the S poly-T. Although the effect of poly-T length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the nenroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523 poly-T. Conclusions: These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription. (C) 2014 The Alzheimer's Association. All rights reserved.