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. 2010 Mar 5;153B(2):409-417.
doi: 10.1002/ajmg.b.30993.

APOE mRNA and protein expression in postmortem brain are modulated by an extended haplotype structure

Lynn M Bekris  1   2 , Nichole M Galloway  1 , Thomas J Montine  3 , Gerard D Schellenberg  4 , Chang-En Yu  1   2
Affiliations

APOE mRNA and protein expression in postmortem brain are modulated by an extended haplotype structure

Lynn M Bekris et al. Am J Med Genet B Neuropsychiatr Genet. .

Abstract

Currently the epsilon4 allele of the apolipoprotein E gene (APOE) is the strongest genetic risk factor for late onset Alzheimer's disease (AD). However, inheritance of the APOE epsilon4 allele is not necessary or sufficient for the development of AD. Genetic evidence suggests that multiple loci in a 70 kb region surrounding APOE are associated with AD risk. Even though these loci could represent surrogate markers in linkage disequilibrium with APOE epsilon4 allele, they could also contribute biological effects independent of the APOE epsilon4 allele. Our previous study identified multiple SNPs upstream from APOE that are associated with cerebrospinal fluid apoE levels, suggesting that a haplotype structure proximal to APOE can influence apoE expression. In this study, we examined apoE expression in human post-mortem brain (PMB), and constructed chromosome-phase-separated haplotypes of the APOE proximal region to evaluate their effect on PMB apoE expression. ApoE protein expression was found to differ among AD brain regions and to differ between AD and control hippocampus. In addition, an extended APOE proximal haplotype structure, spanning from the TOMM40 gene to the APOE promoter, may modulate apoE expression in a brain region-specific manner and may influence AD disease status. In conclusion, this haplotype-phenotype analysis of apoE expression in PMB suggests that either; (1) the cis-regulation of APOE expression levels extends far upstream of the APOE promoter or (2) an APOE epsilon4 allele independent mechanism involving the TOMM40 gene plays a role in the risk of AD.

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Figures

Figure 1
Figure 1
APOE Gene Region Description. Horizontal arrows represent transcriptional orientation for each gene. Vertical arrows represent SNP location. Scale is approximate.
Figure 2
Figure 2
Expression levels of APOE mRNA, protein or mRNA/protein ratio for each brain region in AD patients and controls. APOE mRNA levels do not differ between brain regions (panel A). CB apoE protein levels are higher than FL (p-value, 0.012) or HP (p-value, 0.002) in AD (panel B). AD HP apoE protein levels are lower than control HP (p-value, 0.009) (panel B). AD HP apoE mRNA/protein are significantly higher than control HP (p-value, 0.021) or control CB (p-value, 0.018) (panel C). (cerebellum; CB, frontal lobe; FL, hippocampus; HP, temporal lobe; TL).
Figure 3
Figure 3
Diplotype analysis of APOE expression in PMB. No subjects in the control group carry the H1−(panel A). The H1− diplotype AD apoE protein levels are significantly lower than H1 + displotype control HP (p-value, 0.030) (panel B). The H1 + AD CB has higher apoE protein levels than both the AD FL (p-value, 0.003) and the HP (p-value, 0.007) (panel B). The H1 − AD CB has higher apoE protein levels than H1−AD HP(p-value,0.053) (panel B). The H1 − diplotype AD HP APOE mRNA/protein ratio is significantly higher than H1+ diplotype control HP (p-value, 0.018) (panel C). There is a significant decreasing trend between the H1− AD HP, H1+ AD HP and H1+ control HP (indicated by arrows and dotted line) (p-value. 0.011) (panel C).
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