Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites.
Mol Psychiatry
; 17(2): 223-33, 2012 Feb.
Article
in En
| MEDLINE
| ID: mdl-21403675
ABSTRACT
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) É4 alleles (P(adj)<0.006; OR=1.50 (95% CI 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aß1â42 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, Complement
/
Complement Factor I
/
Polymorphism, Single Nucleotide
/
DNA Copy Number Variations
/
Alzheimer Disease
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
/
Systematic_reviews
Limits:
Aged
/
Aged80
/
Female
/
Humans
/
Male
Language:
En
Journal:
Mol Psychiatry
Journal subject:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Year:
2012
Document type:
Article
Affiliation country:
Belgium