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 (Aβ) 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 Aβ1–40 and Aβ1–42 in 1621 non-demented participants of the population-based Rotterdam Study. In non-demented persons, plasma Aβ concentration reflect levels of Aβ 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 Aβ1–40 and Aβ1–42 levels were assessed using the program Haplo.Stats. Compared with haplotype 1, haplotype 4 was associated with significantly lower levels of plasma Aβ1–40 (β=−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 Aβ1–42 (β=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 Aβ concentration and deposition in the brain.