Genetic Diversity in the Matrix Metalloproteinase Family: Effects on Function and Disease Progression^a

Abstract

Atherosclerosis is an example of a complex trait, where the course of the disease is influenced by a combination of common variation in a constellation of genes and the effect of a wide range of environmental variables. Thus, the underlying disease mechanisms will be modulated by genetic diversity and the effect this diversity has on an individual's response to environmental challenges such as smoking, diet, and exercise. Unlike the consequences of mutations in severe single‐gene disorders on protein function, the impact of individual common, functionally important sequence changes in genes contributing to multifactorial diseases is likely to be very small. The challenge is to dissect the contribution that each of these genes makes to the disease process. We have tackled this by identifying common genetic variants, studying their effects on function, and applying them to the analysis of association in appropriately structured and suitably powered studies. Even with our incomplete understanding of the disease, the list of potential candidate genes we could study is vast; but, we do know from pathological studies that a wide spectrum of structural architecture exists in atherosclerotic plaques, suggesting that remodeling of vascular connective tissue is fundamentally important. Matrix remodeling is controlled by a complex network of cell and matrix interactions, the net outcome of which is the product of a balance between synthetic and degradative processes. Our work has focused on the family of enzymes and inhibitors most directly associated with matrix turnover‐the matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs, tissue inhibitors of MPs). We specifically searched for functionally relevant genetic variants that might modulate the delicate control of matrix turnover. Using these molecular genetic strategies to investigate the impact of natural genetic variation on vascular matrix remodeling has begun to shed new light on the importance of these genes in atherogenesis.

The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer

“…The discovery of polymorphisms in MMP promoters that alter gene expression has revealed strong associations between these genetic variants and increased susceptibility to the development of malignancies and other diseases (Henney et al, 2000;Ye, 2000). The most extensively studied MMP SNP in relation to cancer is the À1607 bp insertion/deletion in the MMP-1 promoter (Rutter et al, 1998;Nishioka et al, 2000;Ghilardi et al, 2001;Zhu et al, 2001;Hinoda et al, 2002;Tower et al, 2002;Wyatt et al, 2002;Zinzindohoue et al, 2005;Elander et al, 2006).…”

Association of Genetic Polymorphisms in Matrix Metalloproteinase-9 and Coronary Artery Disease in the Chinese Han Population: A Case–Control Study

“…Changed expression of MMPs has been implicated in the pathogenesis of several cardiovascular disorders, including atherosclerosis (Newby, 2005). Recent observations suggest that genetic variation affects the expression of MMPs, which may contribute to the occurrence of cardiovascular disease (Henney et al, 2000).…”

Meta-Analysis of <b><i>MMP9</i></b> –1562C/T and the Risk of Coronary Heart Disease

“…Furthermore, it has been observed that T allele carriers in comparison with CC homozygotes were overrepresented in a subgroup of patients with triple-vessel disease [20]. Recent research suggested that –1562C/T affected the expression of MMP9, which may contribute to the occurrence of cardiovascular disease [21]. A common R279Q polymorphism of the MMP9 exon 6 leading to an amino acid substitution in the enzymatic active site has also been described [7,22,23].…”