title: Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes.
abstract: The epsilon4 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 epsilon4 allele was observed relative to that of the epsilon3 and epsilon2 alleles (P<0.0001). Similar differences were observed in brain tissue from confirmed LOAD subjects, and between cortical regions BA10 (frontopolar) and BA20 (inferior temporal). Stratification of epsilon4/epsilon3 allelic expression ratios according to heterozygosity for the -219G>T 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 epsilon4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.
authors.affiliation: Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff , UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bray
authors.forename: Luke
authors.initials: L
authors.lastname: Jehu
authors.forename: Valentina
authors.initials: V
authors.lastname: Moskvina
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Stella
authors.initials: S
authors.lastname: Dracheva
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Paul R
authors.initials: PR
authors.lastname: Buckland
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E