Human Molecular Genetics Advance Access originally published online on July 5, 2007
Human Molecular Genetics 2007 16(18):2199-2208; doi:10.1093/hmg/ddm171
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Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease
1 Division of Clinical Chemistry, Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH , UK, 2 School of Physics and Astronomy, University of Nottingham, University Park, Nottingham NG7 2RD, UK and 3 OPTIMA, Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, Oxford OX1 3PT, UK
* To whom correspondence should be addressed. Tel: +44 1158230724; Fax: +44 1159709167; Email: kevin.morgan{at}nottingham.ac.uk
Received May 11, 2007; Accepted June 28, 2007
The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the regulatory regions of the apolipoprotein E (APOE) gene modify the well-established 
4-associated risk for Alzheimer's disease (AD). Sequencing of the APOE gene regulatory regions revealed four previously reported promoter SNPs and one novel SNP in the previously described macrophage enhancer (ME.1). In addition, we also studied the two classic allelic missense SNPs that define 2/3/4 status in a case–control association study. Analysis of pair-wise linkage disequilibrium (LD) of the five regulatory region SNPs with classic APOE SNPs revealed a previously unreported 7 kb LD block covering the entire APOE gene, part of the promoter and 3' enhancer region. We report here that in a case–control association study (N=719) of the seven SNPs, the genotype at codon 112 captures all the information required to assess disease risk. To explore correlations with quantitative traits, 169 patients were studied in whom rates of cognitive decline were available. In addition to the 4 allele, two regulatory region SNPs were associated with the rate of cognitive decline in AD patients. This study highlights the effect of APOE gene variation on risk of AD and rate of cognitive decline and demonstrates that a single SNP, which confers 4 status, captures all of the risk of developing AD but two SNPs in the regulatory region may affect the rate of cognitive decline in AD patients.