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P1–353: Associaton of VR22 and LRRTM3 variants with late onset Alzheimer's disease (LOAD) and amyloid beta levels
Author(s) -
Ertekin-Taner Nilufer,
Allen Mariet,
Younkin Linda,
Carrasquillo Minerva,
Younkin Samuel,
Greene Matthew H.,
Kashino Mariah,
Singhal Sita,
Dincman Toros,
Petersen Ronald,
Graff-Radford Neill,
Younkin Steven G.
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.731
Subject(s) - single nucleotide polymorphism , snp , biology , genetics , presenilin , gene , allele , genetic association , disease , alzheimer's disease , genotype , medicine
Background: Chromosome 10q links to plasma A 42 levels and risk for LOAD. The VR22 gene on Ch10q has variants that strongly associate with A 42, accounting for most A 42 linkage. VR22 encodes -T catenin which interacts through catenin with presenilin 1. LRRTM3 (leucine rich repeat transmembrane neuronal 3) is a neuronally expressed gene that resides in an intron of VR22. Martin et al. recently reported significant associations of VR22 and LRRTM3 SNPs with LOAD, including some variants that previously associated with A in our series. Objective: To explore the association of VR22 and LRRTM3 with LOAD and A , we analyzed 40 variants in these genes in LOAD case-control series and families. Methods: Four VR22 and two LRRTM3 SNPs which associated or linked with LOAD in the Martin et al. study were analyzed in our series. Many additional putative functional variants within conserved regions of VR22 and LRRTM3 were also tested. Results: Two of the four VR22 SNPs which associated in Martin et al. showed marginal association with AD in our series (p 0.08). The other two VR22 SNPs associated at p 0.3. The major allele of VR22 SNP rs12357560, which strongly associated with high A in our families and with AD in Martin et al., trended towards risk in our case-controls. The rs1925583 SNP in LRRTM3, which associated with LOAD in Martin et al., associated with both LOAD and A in our series. We analyzed a total of 35 SNPs in VR22 and 10 in LRRTM3. Six VR22 variants were significant (p 0.05) in one or more case-control series. Remarkably, 17 VR22 SNPs were significant at p 0.25. Five out of ten LRRTM3 SNPs showed significant association (p 0.05) with LOAD or plasma A . Common ( 1%) LRRTM3 multilocus genotypes significantly associated with LOAD (global empirical p 0.01). Some, but not all of the risky LRRTM3 haplotypes identified in the case-controls associated with elevated A levels in the families. Conclusions: These results suggest that both VR22 and LRRTM3 have independent variants that substantially influence risk for AD and A levels, but validation is needed from analyses of large follow-up series that are currently underway.