Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease

Lambert, Jean‐Charles; Luedecking-Zimmer, Erin; Merrot, Séverine; Hayes, AJ; Thaker, Uma; Desai, Purnima P.; Houzet, Alexia; Hermant, Xavier; Cottel, Dominique; Pritchard, Antonia L.; Iwatsubo, Takeshi; Pasquier, Florence; Frigard, B.; Conneally, P. Michael; Chartier-Harlin, Marie-Christine; DeKosky, Steven T.; Lendon, Corinne; Mann, David G.; Kamboh, M. Ilyas; Amouyel, Philippe

doi:10.1136/jmg.40.6.424

Cited by 38 publications

(28 citation statements)

References 43 publications

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“…Our data underscore the role of cholesterol in the development of AD, and with the incorporation of CETP, the list of genes related to cholesterol transport and catabolism in the brain (APOE, LRP [19], CYP46 [16], ABCA1 [24], ABCA2 [12], OLR1 [11], ACAT1 [25], LDL-R [10]) that have polymorphisms linked to AD continues to grow.…”

Section: Discussionmentioning

confidence: 73%

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

et al. 2005

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Cholesterol regulates the production of amyloid beta (Abeta), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta 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) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 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 epsilon4/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 epsilon4 allele, possibly through modulation of brain cholesterol metabolism.

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Section: Discussionmentioning

confidence: 73%

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

et al. 2005

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“…2 However, no APOE e4-dependence was observed in either of the samples investigated in the latter study. Furthermore, these authors also saw a significant under-representation of the TT-genotype v the CC/CT-genotypes, and this finding was interpreted as a risk effect in carriers of the C-allele v noncarriers.…”

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confidence: 53%

“…While no correlation between this polymorphism and cerebral Ab or tau load was observed in this study, there was evidence of a significantly reduced expression of OLR1 in carriers of the C-allele carriers v non-carriers. 2 Our laboratory has previously tested several AD candidate genes on chromosome 12 for association with AD in one of the largest AD family samples collected to date, the NIMH Genetics Initiative Study sample. [3][4][5][6] Of these, the strongest and most consistent signals observed were obtained with polymorphisms in A2M, which show a strong effect on AD risk, predominantly in families with late-onset AD.…”

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confidence: 99%

No association between a previously reported OLR1 3' UTR polymorphism and Alzheimer's disease in a large family sample

Bertram¹,

Parkinson²,

Mullin³

et al. 2004

Journal of Medical Genetics

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“…6 The LDL receptor gene (LDLR) is located on chromosome 19 (19p13.2), is 45 kb long, and has 18 exons. LDLR has seven functional domains: the promoter translation signal sequence (exon 1), the ligand binding domain (exons 2-6), the epidermal growth factor precursor homology domain (exons [7][8][9][10][11][12][13][14], the O linked sugar domain (exon 15), the membrane spanning domain (exons [16][17], and the cytoplasmic domain (exons [17][18]. 7 More than 600 mutations that are responsible for familial hypercholesterolaemia have been identified in LDLR.…”

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confidence: 99%

Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease

Cheng

Huang

Lanham

et al. 2005

Journal of Medical Genetics

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Background: Multiple genes have been provisionally associated with Alzheimer's disease, including the coding polymorphisms in exons 8 and 13 in the low density lipoprotein receptor gene (LDLR), situated on chromosome 19p13.2. Methods: The sample groups consisted of 180 AD patients and 141 control spouses. We carried out genotyping of LDLR8 and LDLR13. Results: The LDLR8 GG genotype was common, found in 84% of the unaffected control subjects and 91% of the AD patients in our study. There was a ninefold elevation in risk associated with GG:CC versus A-and T-among APOE4+ subjects when compared with APOE42 subjects (odds ratio 9.3; 95% confidence interval 1.8 to 48.2). With the additional information on LDLR polymorphism, we defined an overall 12 fold elevation in risk for APOE4 in combination with LDLR GG:CC (11.9; 2.8 to 50.0; Fisher's exact test, p = 0.0002; standard power 0.999), compared with other subjects lacking all three of these polymorphisms. Conclusion: These results imply a functional interaction between ApoE and LDL receptor proteins that determines risk for Alzheimer's disease.

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Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease

Cited by 38 publications

References 43 publications

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

No association between a previously reported OLR1 3' UTR polymorphism and Alzheimer's disease in a large family sample

Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease

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