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Updated: Jul 3, 2026
Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
Published on: June 9, 2018
Matrix metalloproteinase 3 haplotypes and plasma amyloid beta levels: the Rotterdam Study
Christiane Reitz1, Frank J A van Rooij, Holly D Soares
1Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
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.
Insights
Genetic variations in the matrix metalloproteinase-3 (MMP-3) gene are linked to altered amyloid beta (Abeta) levels in humans. This suggests MMP-3 may influence Alzheimer's disease pathogenesis by affecting Abeta accumulation.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are implicated in amyloid beta (Abeta) protein degradation, a key factor in Alzheimer's disease pathogenesis.
- The association between MMPs and human Abeta levels remains unclear.
- Plasma Abeta levels in non-demented individuals may reflect brain Abeta concentrations.
Purpose of the Study:
- To investigate the relationship between common haplotypes of the matrix metalloproteinase-3 (MMP-3) gene and plasma levels of Abeta(1-40) and Abeta(1-42) in a human population.
- To explore the potential role of MMP-3 genetic variations in modulating Abeta levels, relevant to Alzheimer's disease.
Main Methods:
- Genotyping of four polymorphisms (rs3025058, rs522616, rs563096, rs3025066) in the MMP-3 gene.
- Reconstruction of common MMP-3 haplotypes in 1621 non-demented participants of the Rotterdam Study.
- Statistical analysis using Haplo.Stats to assess associations between MMP-3 haplotypes and plasma Abeta(1-40)/Abeta(1-42) levels, adjusted for age and sex.
Main Results:
- Haplotype 4 of the MMP-3 gene was significantly associated with lower plasma Abeta(1-40) levels (p=0.02).
- Haplotype 2 of the MMP-3 gene was significantly associated with higher plasma Abeta(1-42) levels (p=0.0002).
- These findings indicate a genetic link between MMP-3 variations and human Abeta concentrations.
Conclusions:
- Genetic variations within the MMP-3 gene are associated with differential plasma levels of Abeta(1-40) and Abeta(1-42) in humans.
- MMP-3 may play a role in regulating Abeta levels, potentially influencing Alzheimer's disease risk.
- Modulation of MMP-3 activity or secretion could impact Abeta concentration and brain deposition.
