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Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2885-2892; doi:10.1093/hmg/ddh299
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Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved

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

Nicholas J. Bray1, Luke Jehu1, Valentina Moskvina2, Joseph D. Buxbaum3, Stella Dracheva3, Vahram Haroutunian3,4, Julie Williams1,2, Paul R. Buckland1, Michael J. Owen1 and Michael C. O'Donovan1,*

1Department of Psychological Medicine and 2Biostatistics Bioinformatics Unit, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK, 3Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10021, USA and 4Mental Illness Research, Education and Clinical Centres (MIRECC), Bronx Veterans Affairs Medical Centre, Bronx, New York, NY 10468, USA

Received August 9, 2004; Accepted September 11, 2004

The {varepsilon}4 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 {varepsilon}4 allele was observed relative to that of the {varepsilon}3 and {varepsilon}2 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 {varepsilon}4/{varepsilon}3 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 {varepsilon}4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.

* To whom correspondence should be addressed. Tel: +44 2920743242; Fax: +44 2920746554; Email: odonovanmc{at}cardiff.ac.uk


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