title: A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations.
abstract: Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).
authors.affiliation: Department NVS, KI-Alzheimer Disease Research Center, Karolinska Institutet, Huddinge, SE-14157 Stockholm, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Keller
authors.forename: Charlotte
authors.initials: C
authors.lastname: Murphy
authors.forename: Hui-Xin
authors.initials: HX
authors.lastname: Wang
authors.forename: Laura
authors.initials: L
authors.lastname: Fratiglioni
authors.forename: Maria
authors.initials: M
authors.lastname: Olin
authors.forename: Mats
authors.initials: M
authors.lastname: Gafvels
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.forename: Steve
authors.initials: S
authors.lastname: Meaney
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D053327:Apolipoprotein E4 / Q000235:genetics; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D014162:Transfection / Q000379:methods
chemical_list: D053327:Apolipoprotein E4; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases