Association of Polymorphisms of the Tissue Inhibitors of Metalloproteinases- 1 and -2 with Alzheimer’s Disease in Taiwan

Background: Alzheimer’s disease (AD) leads to progressive neuronal loss and cognitive and behavioral decline in the aging population. Matrix metalloproteinases (MMPs) and associated tissue inhibitors of metalloproteinases (TIMPs) are involved in remodeling the extracellular matrix. Amyloid beta-42 interrupts the integrity of the neurovascular unit and induces a toxic reaction affecting neurons. Objective: This study investigated the relationships among genetic variants of the MMP-2, MMP-9, TIMP-1, and TIMP-2 genes and AD. Methods: Two hundred and thirteen probable AD patients and 315 control participants of the Taiwan population were recruited for primary investigations, and we used the data of 763 participants from the Taiwan Biobank (TWB), as controls, for validation. Multivariable logistic regression was performed with adjustments for age, sex, hypertension, diabetes mellitus (DM), and alcohol consumption. The associations between the genotypes and allele frequencies and the SNP-associated AD hereditary models were analyzed using the SNPassoc package for R. We performed a permutation test with 1,000 replicates for the empirical estimates. Results: A total of 213 probable AD patients and 315 control participants were recruited. The frequency of the A alleles in rs7503726 (G > A) in TIMP-2 was lower in the AD patients (p < 0.01). The frequencies of the TIMP-2 rs7503726 G/A and A/A genotypes were also significantly lower in the AD patients (p = 0.02) than in the controls and TWB. The TIMP-2 rs7503726 AA genotype was associated with a protective effect of AD in additive and recessive hereditary models (OR = 0.54, 95% CI: 0.32 - 0.92, p = 0.02; OR = 0.68, 95% CI: 0.50 - 0.92, p = 0.01, respectively). Conclusion: The TIMP-2 rs7503726 AA genotype was inversely correlated with AD susceptibility, and the presence of minor alleles of rs7503726 (A allele) have protective effects against AD.