Your browser doesn't support javascript.
loading
Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.
Brouwers, N; Van Cauwenberghe, C; Engelborghs, S; Lambert, J-C; Bettens, K; Le Bastard, N; Pasquier, F; Montoya, A Gil; Peeters, K; Mattheijssens, M; Vandenberghe, R; Deyn, P P De; Cruts, M; Amouyel, P; Sleegers, K; Van Broeckhoven, C.
Afiliação
  • Brouwers N; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium.
Mol Psychiatry ; 17(2): 223-33, 2012 Feb.
Article em En | MEDLINE | ID: mdl-21403675
Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ɛ4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1₋42 levels, suggesting a role for the CR1 protein in Aß metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de Complemento / Fator I do Complemento / Polimorfismo de Nucleotídeo Único / Variações do Número de Cópias de DNA / Doença de Alzheimer Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Aged / Aged80 / Female / Humans / Male Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores de Complemento / Fator I do Complemento / Polimorfismo de Nucleotídeo Único / Variações do Número de Cópias de DNA / Doença de Alzheimer Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limite: Aged / Aged80 / Female / Humans / Male Idioma: En Ano de publicação: 2012 Tipo de documento: Article