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

Bray, Nicholas John ORCID: https://orcid.org/0000-0002-4357-574X, Jehu, Luke, Moskvina, Vanentina, Buxbaum, Joseph D., Dracheva, Stella, Haroutunian, Vahram, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Buckland, Paul Robert, Owen, Michael John ORCID: https://orcid.org/0000-0003-4798-0862 and O'Donovan, Michael Conlon ORCID: https://orcid.org/0000-0001-7073-2379 2004. Allelic expression of APOE in human brain: effects of epsilon status and promoter haplotypes. Human Molecular Genetics 13 (22) , pp. 2885-2892. 10.1093/hmg/ddh299

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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 (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 ε4/ε3 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 ε4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General)
Publisher:	Oxford University Press
ISSN:	1460-2083
Last Modified:	25 Oct 2024 01:19
URI:	https://orca.cardiff.ac.uk/id/eprint/57741

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