Polymorphisms in MMP Family and TIMP Genes and Carotid Artery Intima-Media Thickness

Abstract

Genetic variation in a number of MMP and TIMP genes have been implicated as risk factors for atherosclerosis, although such studies have been generally small and produced conflicting results. We have therefore sought to address this issue in a large, well-phenotyped community population to assess the effect of a number of polymorphisms in both MMP and TIMP genes on carotid artery intima-media thickness (IMT). In a community population (n=1000), IMT was determined using ultrasound in the common carotid artery, carotid bulb, and bifurcation. Eight polymorphisms in 6 MMP genes were genotyped (MMP1 A-519G, MMP2 C-1306T, MMP2 C-735T, MMP3 -1171 5A/6A, MMP9 R279Q, TIMP2 G853A, TIMP3 A-915G, and T-1296C) and assessed for their effect on carotid IMT alone and by interaction with common cardiovascular risk factors. An association was found between MMP9 R279Q and internal carotid artery bulb IMT (P=0.002), but there was no linear trend between allele number and IMT and no association with common carotid artery or bulb IMT. In addition, 3 interactions were found between polymorphisms and hypertension (MMP1 A-519G, MMP3 5A/6A, TIMP3 T-1296C), the latter 2 of which showed a significant trend test for linearity with increasing copy number and increased internal carotid artery bulb IMT. All remained significant after correction for multiple testing. Our findings provide little support for genetic variants of MMP as direct risk factors for IMT. However, the interaction findings between MMP variants and hypertension suggest that hypertensive carriers of these alleles may be at greater risk for increased IMT and future cardiovascular disease. These findings need replication in hypertensive populations to assess their effects more fully.