title: Matrix metalloproteinase 3 haplotypes and plasma amyloid beta levels: the Rotterdam Study.
abstract: Experimental studies suggest that matrix metalloproteinases (MMPs) are involved in the degradation of amyloid beta (Abeta) protein which plays a key role in the pathogenesis of Alzheimer's disease. Whether MMPs are associated with changes in beta amyloid levels in humans remains unclear. We related common haplotypes within the gene encoding MMP-3 with plasma levels of Abeta(1-40) and Abeta(1-42) in 1621 non-demented participants of the population-based Rotterdam Study. In non-demented persons, plasma Abeta concentration reflect levels of Abeta in the brain. DNA was genotyped for polymorphisms 1187 (5A6A, rs3025058), 2092A>G (rs522616), 9775T>A (rs563096) and 6658T>C (rs3025066) and haplotypes reconstructed (coding from 1187 (5A6A), 2092A>G, 9775T>A and 6658T>C: haplotype 1=5A-A-T-T, haplotype 2=6A-G-T-T, haplotype 3=6A-A-T-T, haplotype 4=6A-A-A-T and haplotype 5=5A-A-T-C). Then the associations of these haplotypes with plasma Abeta(1-40) and Abeta(1-42) levels were assessed using the program Haplo.Stats. Compared with haplotype 1, haplotype 4 was associated with significantly lower levels of plasma Abeta(1-40) (beta=-8.04, 95% CI (-14.79; -1.28), p=0.02) after adjusting for age and sex. Haplotype 2 was associated with significantly higher levels of plasma Abeta(1-42) (beta=3.70, 95% CI (1.75; 5.65), p=0.0002). Our observations suggest that variation in the gene encoding MMP-3 is associated with changes in amyloid beta levels in humans. Factors modulating secretion or activity of MMP-3 may have the potential to influence the amount of Abeta concentration and deposition in the brain.
authors.affiliation: Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.forename: Frank J A
authors.initials: FJ
authors.lastname: van Rooij
authors.forename: Holly D
authors.initials: HD
authors.lastname: Soares
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: Monique M B
authors.initials: MM
authors.lastname: Breteler
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000097:blood* / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D008875:Middle Aged; D009426:Netherlands; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D019278:Matrix Metalloproteinase 3