Variation in the human matrix metalloproteinase-9 gene is associated with arterial stiffness in healthy individuals.
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).


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 approximately 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.
Yasmin
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Box 110, Cambridge CB2 2QQ, UK. my105@medschl.cam.ac.uk
McEniery
Carmel M
CM
O'Shaughnessy
Kevin M
KM
Harnett
Patrick
P
Arshad
Asif
A
Wallace
Sharon
S
Maki-Petaja
Kaisa
K
McDonnell
Barry
B
Ashby
Mike J
MJ
Brown
John
J
Cockcroft
John R
JR
Wilkinson
Ian B
IB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001120:Arginine; D001158:Arteries / Q000503:physiopathology*; D001783:Blood Flow Velocity; D015331:Cohort Studies; D004548:Elasticity; D014644:Genetic Variation; D005973:Glutamine; D006579:Heterozygote; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D010196:Pancreatic Elastase / Q000097:blood; D011110:Polymorphism, Genetic; D011674:Pulse; D012016:Reference Values; D012044:Regression Analysis
D005973:Glutamine; D001120:Arginine; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9