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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1799.)
© 2006 American Heart Association, Inc.

Vascular Biology

Variation in the Human Matrix Metalloproteinase-9 Gene Is Associated With Arterial Stiffness in Healthy Individuals

Yasmin; Carmel M. McEniery; Kevin M. O’Shaughnessy; Patrick Harnett; Asif Arshad; Sharon Wallace; Kaisa Maki-Petaja; Barry McDonnell; Mike J. Ashby; John Brown; John R. Cockcroft; Ian B. Wilkinson

From the Clinical Pharmacology Unit (Y., C.M.M., K.M.O., P.H., A.A., S.W., K.M.-P., M.J.A., I.B.W.), University of Cambridge, Addenbrooke’s Hospital, Cambridge; the Department of Cardiology (B.M., J.R.C.), University of Wales College of Medicine, Cardiff; and Trinity College (J.B.), Cambridge, UK.

Correspondence to Dr Yasmin, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital Box 110, Cambridge CB2 2QQ, UK. E-mail my105{at}medschl.cam.ac.uk

Background— Arterial stiffness is an important determinant of cardiovascular risk. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes including serine proteases and matrix metalloproteinases (MMPs). Serum MMP-9 levels correlate with arterial stiffness and predict cardiovascular risk. Polymorphisms in the MMP-9 gene are also associated with large artery function in subjects with coronary artery disease. Therefore, we investigated the influence of known MMP-9 (–1562C>T, R279Q) polymorphisms on arterial stiffness in a large cohort of healthy individuals (n=865).

Methods and Results— Aortic pulse wave velocity (PWV) and augmentation index were assessed. Supine blood pressure, biochemical markers, MMP-9 levels, and serum elastase activity (SEA) were also determined. Genomic DNA was extracted and genotyping performed. Aortic PWV, serum MMP-9, and SEA were higher in carriers of the rare alleles for the –1562C>T and R279Q polymorphisms. These polymorphisms were also associated with aortic PWV after correction for other confounding factors. Stepwise regression models with known or likely determinants of arterial stiffness revealed that 60% of the variability in aortic PWV was attributable to age, mean arterial pressure, and genetic variants (P<0.001).

Conclusions— We have demonstrated for the first time that aortic stiffness and elastase activity are influenced by MMP-9 gene polymorphisms. This suggests that the genetic variation in this protein may be involved in the process of large artery stiffening.

We examined the influence of known MMP-9 polymorphisms on arterial stiffness and elastases in a large cohort of healthy individuals. Aortic stiffness and serum elastases are significantly influenced by MMP-9 polymorphisms, suggesting that genetic variation in this protein may be involved in the process of large artery stiffening.

Key Words: aortic pulse wave velocity • augmentation index • MMP-9 gene polymorphisms • MMP-9 levels • serum elastase activity

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