on March 6, 2003
Published online before print March 6, 2003, doi: 10.1161/01.ATV.0000065196.61663.8D
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Submitted on January 27, 2003
Accepted on February 11, 2003
Progression of Atherosclerosis Is Associated With Variation in the 
1-Antitrypsin Gene
Philippa J. Talmud *;
From the Centre for Cardiovascular Genetics (P.J.T., S.M., D.M.F., S.E.H.), Department of Medicine, British Heart Foundation Laboratories, Royal Free and University College Medical School, London, UK; The Toronto Hospital (G.S.), Toronto, Ontario, Canada; ZetaGen Ltd (D.B.W.), Department of Biosciences, University of Hertfordshire, Hatfield, Herts, UK; Centre for Structural Biology (S.N.), Department of Biochemistry, University College London, UK; School of Biochemistry & Molecular Biology (R.J.), University of Leeds, UK; Division of Cardiology (M.-R.T., M.H.F., M.S.N., M.S.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Medicine and Biocenter Oulu (Y.A.K.), Oulu University Hospital and University of Oulu, Finland; and Department of Medicine (A.P.), Tampere University Hospital, Tampere, Finland.
* To whom correspondence should be addressed. E-mail: p.talmud{at}ucl.ac.uk.
Objective--
1-Antitrypsin (AAT) protects elastic tissue and may play a role in atherogenesis. The association of atherosclerosis progression with common AAT variants was considered in 2 clinical trials.
Methods and Results--We examined the association of AAT V213A, S and Z deficiency alleles, and the functional 3' UTR 11478G>A with change in minimal luminal diameter, a measure of focal disease, in the Lopid Coronary Angiography Trial gemfibrozil study of post-bypass men. S or Z carriers (n=14) showed strong progression of disease on placebo (11.5%) but responded well to treatment (3% regression). 11478A carriers treated with placebo or gemfibrozil showed significantly more disease progression (n=8, -14.5% and n=16, -4.0%, respectively) than 11478GG men (n=107, -7.0% and n=108, -1.4%, respectively; overall, P=0.003). VV213 men treated with gemfibrozil (n=68) showed -4.8% progression, whereas A213 carriers (n=55) showed +1.4% regression of disease (P=0.001). No V213A effect was seen on placebo (P=0.11). In the Diabetes Atherosclerosis Intervention Study fenofibrate trial of angiographic progression in type 2 diabetes, the association of 11478A with increased disease progression was confirmed in the treatment group, but not the on-treatment A213 association with regression, suggesting a pharmacogenetic difference.
Conclusions--Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.
Key words:
1-antitrypsin •
gene variants •
atherosclerosis progression •
fibrates
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