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 ε3/ε3 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 neuroblastoma 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.
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Colton
C
Linnertz
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Lauren
L
Anderson
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA.
William
W
Gottschalk
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA.
Donna
D
Crenshaw
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA.
Michael W
MW
Lutz
Institute for Genome Sciences & Policy, Duke University Medical Center, Durham, NC, USA.
Jawara
J
Allen
Institute for Genome Sciences & Policy, Duke University Medical Center, Durham, NC, USA.
Sunita
S
Saith
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Mirta
M
Mihovilovic
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA.
James R
JR
Burke
Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA.
Kathleen A
KA
Welsh-Bohmer
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA; Zinfandel Pharmaceuticals, Chapel Hill, NC, USA.
Allen D
AD
Roses
Division of Neurology at the Department of Medicine, Duke University Medical Center, Durham, NC, USA; Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC, USA; Institute for Genome Sciences & Policy, Duke University Medical Center, Durham, NC, USA. Electronic address: o.chibafalek@duke.edu.
Ornit
O
Chiba-Falek
D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009778:Occipital Lobe / Q000378:metabolism*; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism*; D014162:Transfection
D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D012333:RNA, Messenger; C400783:TOMM40 protein, human
Alzheimer’s disease; Apolipoprotein E; Messenger RNA expression; Poly-T polymorphism; TOMM40; Transcription regulation