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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:644.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Progression of Atherosclerosis Is Associated With Variation in the ₁-Antitrypsin Gene

Philippa J. Talmud; Steve Martin; George Steiner; David M. Flavell; David B. Whitehouse; Sylvia Nagl; Richard Jackson; Marja-Riitta Taskinen; M. Heikki Frick; Markku S. Nieminen; Y. Antero Kesäniemi; Amos Pasternack; Steve E. Humphries; Mikko Syvänne and the Diabetes Atherosclerosis Intervention Study Investigators

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.

Correspondence to Philippa J. Talmud, Centre for Cardiovascular Genetics, Department of Medicine, British Heart Foundation Laboratories, Rayne Building, Royal Free and University College Medical School, 5 University St, London WC1E 6JF, UK. 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 gemfibrozil-treated 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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