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Evidence supporting a role for the calcium‐sensing receptor in Alzheimer disease
Author(s) -
Conley Yvette P.,
Mukherjee Ankur,
Kammerer Candace,
DeKosky Steven T.,
Kamboh M. Ilyas,
Finegold David N.,
Ferrell Robert E.
Publication year - 2009
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30896
Subject(s) - disease , calcium , alzheimer's disease , calcium sensing receptor , neuroscience , receptor , psychology , medicine , calcium metabolism
The calcium‐sensing receptor (CASR) is a G‐protein coupled, transmembrane receptor that responds to changes in Ca 2+ levels. We hypothesized that the CASR could have a role in Alzheimer disease (AD) given expression of the CASR in brain, knowledge that calcium dysregulation promotes susceptibility to neuronal cell damage, the important role that the CASR plays in calcium regulation, and the fact that systemic calcium homeostasis and G‐protein signal transduction are altered in AD patients. To investigate the association of CASR variation in AD susceptibility, we genotyped a polymorphic dinucleotide repeat marker within intron 4, one SNP within the promoter region and three non‐synonymous SNPs within exon 7 of the CASR gene and tested for association analysis, using a well‐characterized cohort of AD cases (n = 692) and controls (n = 435). The dinucleotide repeat polymorphism was significantly associated with AD status (OR = 1.62; 95% CI: 1.27–2.07, P = 0.00037, Bonferroni corrected P = 0.0011) and the three non‐synonymous SNP haplotype was boarderline associated with AD status ( P = 0.032, Bonferroni corrected P = 0.096). Stratifying by APOE4 allele carrier status revealed that the significant association was only in non‐APOE4 carriers (OR of 1.90; 95% CI: 1.37–2.62, P = 0.0001). We also investigated whether apoE or β amyloid could activate the calcium‐sensing receptor. The receptor activation assays revealed that apoE as well as β amyloid activated the CASR and that the level of activation appeared to be isoform dependent for apoE. These data support our hypothesis that the CASR has a role in AD susceptibility, particularly in individuals without an APOE4 allele. © 2008 Wiley‐Liss, Inc.