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The β-amyloid peptide may play a central role in Alzheimer's disease (AD) pathogenesis. We have evaluated variants in seven Aβ-degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, and TF) for association with AD risk in the Genetic and Environmental Risk in Alzheimer's Disease Consortium 1 (GERAD1) cohort, and with three cognitive phenotypes in the Lothian Birth Cohort 1936 (LBC1936), using 128 and 121 SNPs, respectively. In GERAD1, we identified a significant association between a four-SNP intragenic ECE1 haplotype and risk of AD in individuals that carried at least one APOE ε4 allele (P = 0.00035, odds ratio = 1.61). In LBC1936, we identified a significant association between a different two-SNP ECE1 intragenic haplotype and non-verbal reasoning in individuals lacking the APOE ε4 allele (P = 0.00036, β = -0.19). Both results showed a trend towards significance after permutation (0.05 < P < 0.10). A follow-up cognitive genetic study evaluated the association of ECE1 SNPs in three additional cohorts of non-demented older people. Meta-analysis of the four cohorts identified the significant association (Z < 0.05) of SNPs in the ECE-1b promoter with non-verbal reasoning scores, particularly in individuals lacking the APOE ε4 allele. Our genetic findings are not wholly consistent. Nonetheless, the AD associated intronic haplotype is linked to the 338A variant of known ECE1b promoter variant, 338C>A (rs213045). We observed significantly less expression from the 338A variant in two human neuroblastoma cell lines and speculate that this promoter may be subject to tissue-specific regulation.

Original publication

DOI

10.1002/ajmg.b.32073

Type

Journal article

Journal

Am J Med Genet B Neuropsychiatr Genet

Publication Date

09/2012

Volume

159B

Pages

696 - 709

Keywords

Aged, Aging, Alzheimer Disease, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Cognition, Cohort Studies, Endothelin-Converting Enzymes, Female, Genetic Predisposition to Disease, Humans, Male, Meta-Analysis as Topic, Metalloendopeptidases, Middle Aged, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Proteolysis, Risk Factors