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

Authors: Bray, Nicholas J.¹; Jehu, Luke¹; Moskvina, Valentina²; Buxbaum, Joseph D.³; Dracheva, Stella³; Haroutunian, Vahram³; Williams, Julie¹; Buckland, Paul R.¹; Owen, Michael J.¹; O'Donovan, Michael C.¹

Source: Human Molecular Genetics, Volume 13, Number 22, 15 November 2004 , pp. 2885-2892(8)

Publisher: Oxford University Press

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Abstract:

The

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 epsiv

4 allele was observed relative to that of the epsiv

3 and

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 epsiv

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 epsiv

4 haplotype, but there are additional, small, cis-acting influences associated with promoter genotype.

Keywords: Apoptosis; Bcl-2; chloroplast; herbicide

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddh299

Affiliations: 1: Department of Psychological Medicine and 2: Biostatistics Bioinformatics Unit, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK, 3: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10021, USA and

Publication date: 2004-11-15

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

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