Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele
- 267 Downloads
Cholesterol regulates the production of amyloid beta (Aβ), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Aβ in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C–629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) ε4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE ε4 carriers, homozygous for the CETP (–629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01–5.37), than homozygous and heterozygous carriers of the CETP (–629) C allele (odds ratio 7.12, 95% CI 4.51–11.24, P for APOE ε4/CETP (–629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE ε4 allele, possibly through modulation of brain cholesterol metabolism.
Key wordscholesteryl ester transfer protein Alzheimer's disease cholesterol apolipoprotein E polymorphism
Unable to display preview. Download preview PDF.
- 3.Blankenberg S, Rupprecht HJ, Bickel C, Jiang XC, Poirier O, Lackner KJ, Meyer J, Cambien F, Tiret L (2003) Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. J Am Coll Cardiol 41:1983–1989CrossRefPubMedGoogle Scholar
- 6.Dachet C, Poirier O, Cambien F, Chapman J, Rouis M (2000) New functional promoter polymorphism, CETP (–629), in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels. Role of Sp1/Sp3 in transcriptional regulation. Arterioscler Thromb Vasc Biol 20:507–515PubMedGoogle Scholar
- 11.Lambert JC, Luedecking–Zimmer E, Merrot S, Hayes A, Thaker U, Desai P, Houzet A, Hermant X, Cottel D, Pritchard A, Iwatsubo T, Pasquier F, Frigard B, Conneally PM, Chartier– Harlin MC, DeKosky ST, Lendon C, Mann D, Kamboh MI, Amouyel P (2003) Association of 3'–UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease. J Med Genet 40:424–430CrossRefPubMedGoogle Scholar
- 12.Macé S, Cousin E, Ricard S, Génin E, Spanakis E, Lafargue–Soubigou C, Génin B, Fournel R, Roche S, Haussy G, Massey F, Soubigou S, Bréfort G, Benoit P, Brice A, Campion D, Hollis M, Pradier L, Benavides J, Deleuze JF (2005) ABCA2 is a strong genetic risk factor for early–onset Alzheimer's disease. Neurobiol Dis 18:119–125PubMedGoogle Scholar
- 13.McKhaan G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer's disease: Report of the NINCDA–ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34:934–944Google Scholar
- 16.Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, Iakovidou V, Maddalena A, Lütjohann D, Ghebremedhin E, Hegi T, Pasch T, Träxler M, Brühl A, Benussi L, Binetti G, Braak H, Nitsch RM, Hock C (2003) Increased brain β–amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol 60:29–35PubMedGoogle Scholar
- 19.Sánchez–Guerra M, Combarros O, Infante J, Llorca J, Berciano J, Fontalba A, Fernández–Luna JL, Peña N, Fernández– Viadero C (2001) Case–control study and meta–analysis of low density lipoprotein receptor–related protein gene exon 3 polymorphism in Alzheimer's disease. Neurosci Lett 316:17–20PubMedGoogle Scholar
- 25.Wollmer MA, Streffer JR, Tsolaki M, Grimaldi LME, Lütjohann D, Thal D, von Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A (2003) Genetic association of acyl–coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease. Mol Psychiatry 8:635–638CrossRefPubMedGoogle Scholar