Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes

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Abstract
The ε4 haplotype of APOE is the only undisputed genetic risk factor for late-onset Alzheimer's disease (LOAD). It has been proposed that at least two other polymorphisms in the promoter of the APOE gene (−219G>T and −491A>T) might also contribute to disease susceptibility, and modulate the impact of structural changes in the ApoE protein, by altering its expression. In order to assess the extent of cis-acting influences on APOE expression in human brain, highly quantitative measures of allele discrimination were applied to cortical RNA from individuals heterozygous for the epsilon alleles. A small, but significant, increase in the expression of ε4 allele was observed relative to that of the ε3 and ε2 alleles (PT promoter polymorphism revealed significantly lower relative expression of haplotypes containing the −219T allele (P=0.02). Our data indicate that, in human brain, most of the cis-acting variance in APOE expression is accounted for by the ε4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.